Next Article in Journal
Prognosis in Chronic Myeloid Leukemia: Baseline Factors, Dynamic Risk Assessment and Novel Insights
Previous Article in Journal
The Role of Aquaporins in Spinal Cord Injury
Previous Article in Special Issue
Autophagosome Biogenesis
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
Cells
Volume 12
Issue 13
10.3390/cells12131702
cells-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors

by
Eloïne Bestion
1,*,
Eric Raymond
1,2,
Soraya Mezouar
1,3,† and
Philippe Halfon
1,†
1
Genoscience Pharma, 13006 Marseille, France
2
Department of Medical Oncology, Paris Saint-Joseph Hospital Group, 75014 Paris, France
3
Établissement Français du Sang, Provence Alpes Côte d’Azur et Corse, Marseille, France; «Biologie des Groupes Sanguins», Aix Marseille Univ-CNRS-EFS-ADÉS, 13005 Marseille, France
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Cells 2023, 12(13), 1702; https://doi.org/10.3390/cells12131702
Submission received: 19 May 2023 / Revised: 12 June 2023 / Accepted: 21 June 2023 / Published: 23 June 2023
(This article belongs to the Special Issue Exclusive Review Papers in Autophagy)
Browse Figures
Versions Notes

Abstract

:
Autophagy is a highly conserved and natural degradation process that helps maintain cell homeostasis through the elimination of old, worn, and defective cellular components, ensuring proper cell energy intake. The degradative pathway constitutes a protective barrier against diverse human diseases including cancer. Autophagy basal level has been reported to be completely dysregulated during the entire oncogenic process. Autophagy influences not only cancer initiation, development, and maintenance but also regulates cancer response to therapy. Currently, autophagy inhibitor candidates mainly target the early autophagy process without any successful preclinical/clinical development. Lessons learned from autophagy pharmaceutical manipulation as a curative option progressively help to improve drug design and to encounter new targets of interest. Combinatorial strategies with autophagy modulators are supported by abundant evidence, especially dealing with immune checkpoint inhibitors, for which encouraging preclinical results have been recently published. GNS561, a PPT1 inhibitor, is a promising autophagy modulator as it has started a phase 2 clinical trial in liver cancer indication, combined with atezolizumab and bevacizumab, an assessment without precedent in the field. This approach paves a new road, leading to the resurgence of anticancer autophagy inhibitors as an attractive therapeutic target in cancer.

1. Introduction

Autophagy is subdivided into three main types: macroautophagy, microautophagy, and chaperone-mediated autophagy. All of them work on the removal of unnecessary or dysfunctional cellular components, ensuring the maintenance of cellular homeostasis and survival [1,2]. In this review, macroautophagy, hereafter referred to as autophagy, is discussed.
The autophagy mechanism, active at the basal level in most healthy cell types [3,4], is a highly regulated pathway accompanied by tens of autophagy-related (ATG) genes encoding for crucial autophagy proteins [5,6]. Some of which, referred to as the ‘core’ molecular machinery, are particularly essential for autophagy-related compartments formation. The first central autophagy body is the autophagosome, a double-membrane structure able to sequester cellular components that will thereafter merge with the second primordial autophagy body, the lysosome. This acidic vesicle encompasses a variety of hydrolases able to breakdown embedded cellular components into essential products. They are thereafter discharged into the cytoplasm and used for the biosynthesis of new components, enabling cell sustainability. As a crucial survival mechanism, the autophagy molecular pathway has been extensively studied (Figure 1).
Autophagy deregulation is associated with various human pathogeneses such as cardiovascular diseases, immune diseases, and cancers [5,7,8,9,10]. Autophagy baseline level fluctuations were first described in cancer cells in the late 1970s [11,12], then demonstrated to be observable during the entire oncogenic process [13,14] (Figure 2). Paradoxical roles of autophagy in tumor suppression and tumor promotion rapidly surfaced, depending on not only the autophagy basal level but the tumor type, disease stage, and genetic background as well [6,15,16]. It is indeed widely admitted that autophagy behaves as a tumor-suppressor mechanism at the very early stages of tumorigenesis [13,17], with its deficiency enabling tumor formation. Conversely, once a tumor has formed and grows, proficient autophagy instead provides assistance to cancer cells to respond to various environmental stresses such as nutrient deprivation, hypoxia, metabolic stress, and detachment from the extracellular matrix (ECM), ensuring their survival and the formation of metastatic sites [16,18,19,20,21,22]. It is thus commonly admitted that for most advanced cancers, the autophagy level is promulgated, promoting cancer progression. Autophagy disruption has been either connected to core ATG genes alteration, including BECN1, ATG1, ATG5, ATG7, ULK1, or Atg16L1 [4,23,24,25,26,27], and, more recently, the lysosomal enzyme palmitoyl-protein thioesterase 1 (PPT1) [28,29,30].
Autophagy machinery has therefore turned out to be an attractive therapeutic target in cancer, especially for dealing with process inhibition when it comes to advanced stages. Recently, an autophagy combinatorial strategy with immunotherapies has been put forward since studies have demonstrated that the use of autophagy inhibitors triggers immune checkpoint inhibitors (ICIs) efficacy, thus improving anticancer response [31,32,33]. Also, pharmacologic autophagy inhibition participates in immune response recovery, with it being an attractive approach to fight cancer therapeutic resistance [30,34].
A review of the latest and major small molecules able to inhibit the autophagy mechanism has been realised in regard to their mode of action and both their preclinical and clinical results. Recent advances dealing with the relevance of the autophagy inhibitor combination strategy are as well examined, focusing on the use of immune checkpoint inhibitors. We have further discussed the new identified autophagy targets for drug development, opening up on targeted protein degradation strategies.

2. Targeting Cancer with Autophagy Inhibitors

A diverse range of autophagy inhibitors have been developed and tested throughout the last few decades. Most of them turned out to be key tools for the mechanistic study of the autophagy process and for novel therapeutic agents’ design since they displayed significant side effects, thus obstructing their application in clinical trials [35,36,37]. A few autophagy inhibitors are currently under the spotlight as cancer drug candidates. Hereafter, the main and latest tested inhibitory molecules according to their targeted autophagy-related factors are reported.

2.1. ULK1/2 Inhibitors

The Unc-51-like kinase 1 (ULK1) complex consists of ULK1 and ULK2 proteins and the protein partners ATG13, ATG101, and FIP200 to mediate MTOR signals. Because the complex is required during the early steps of autophagosome biogenesis [38,39,40], the developed ULK1/2 inhibitors block early autophagy mainly through the inhibition of the ULKs’ kinase activity. Some of them compete with the ATP binding site, including MRT67307 and MRT68921, an improved MRT67307-derivative compound [41]. Both of the last two reversible kinase inhibitors were found to specifically block the function of TANK-binding kinase 1 (TBK1) [41,42]. They are able to disrupt autophagosome maturation in mouse embryonic fibroblasts (MEFs), blocking autophagic flux [43].
SBI-0206965, a highly specific inhibitor of ULK1 developed from a focal adhesion kinase (FAK) inhibitor, suppresses ULK1-mediated phosphorylation events in cells [44]. The compound has displayed tumor growth inhibition properties both in vitro and in vivo in various cancer types via dual autophagy and apoptosis pathways [44,45,46,47]. SBI-0206965 is also a direct inhibitor of AMP-activated protein kinase (AMPK) that activates not only the ULK complex [48] but that of FAK as well [44], making its specificity disputable.
More recently, Martin et al. reported ULK-100 and ULK-101 small molecules and demonstrated their in vitro superior potency and selectivity over SBI-0206965 [49]. The molecules were able to sensitize KRAS mutant lung cancer cells to nutrient stress, and ULK-101 allowed the inhibition of both the nucleation of autophagic vesicles and turnover.
DCC-3116 was demonstrated to be a potent and selective dual inhibitor of ULK1 and ULK2, acting at the nanomolar range [50]. The small molecule was further outlined to block autophagosome formation and lysosomal degradation. The compound is particularly attractive in multiple RAS cancer cell lines including lung, pancreatic, colorectal (CRC), and melanoma cancer. Interestingly, DCC-3116 was shown to inhibit compensatory autophagy from KRAS G12C inhibitors in vitro [51]. DCC-3116, as monotherapy and in combination with trametinib, binimetinib, or sotorasib, is currently under phase 1/2 clinical trials in patients with advanced or metastatic solid tumors exhibiting an RAS/mitogen-activated protein kinase (MAPK) pathway mutation (NCT04892017).

2.2. Vacuolar Protein Sorting 34 (VPS34) Inhibitors

Pasquier et al. worked on the discovery of new specific VPS34 kinase inhibitors identifying a series of tetrahydropyrimidopyrimidinone derivatives [52], starting with hit compound 1a to compound 31 after medicinal chemistry optimization. Some of them showed potent antiproliferative and apoptotic effects, both in vitro and in vivo in various cancer types [53,54,55,56].
Recently, aurone derivative 1a, an ATP-competitive inhibitor of the VPS34 inhibitor, has been demonstrated to suppress autophagy in cell-based assays [57] and in in vivo models [58].
Considering breast cancer, SB02024 blocks autophagy in vitro, reduces xenograft growth in two breast cancer cell lines in vivo, and significantly improves sensitivity to sunitinib and erlotinib [59]. Noman et al.’s study revealed, using SB02024 or SAR405, a decrease in tumor growth and improved mice survival in melanoma and CRC tumors [60]. Noman laboratory also revealed that targeting VPS34 in animal models turns cold tumors into hot, inflamed tumors in melanoma and CRC, thus enhancing the efficacy of anti-programmed death-ligand 1 (PD-L1)/programmed cell death-1 (PD-1) blockade [60]. The combinatorial strategy indeed enhances the infiltration of CD8+ T cells and M1 macrophages into the tumor site. SAR405 additionally hampers autophagy and synergizes with MTOR inhibition in renal tumor cells [61]. The principal issue with the use of VPS34 inhibitors is their implication in non-autophagic late endocytic trafficking [62], compromising drug specificity. To date, none of the abovementioned inhibitors has entered clinical trials.

2.3. V-ATPase Inhibitors

Vacuolar-ATPase (V-ATPase) is a proton pump responsible for cellular homeostasis. The multi-subunit transmembrane complex controls, among others, lysosome acidification, indirectly regulating autophagic flux [63]. The most commonly employed vacuolar-H+ ATPase inhibitor encompasses pepstatin A, leupeptin, E64d, salinomycin, and bafilomycin which thereby alkalinize lysosomal compartment, blocking autophagosome–lysosome fusion [64]. Those V-ATPase inhibitors, however, display tolerability and pharmacological issues limiting their use to laboratory tools.
Recently, a panel of Ras-mutant preclinical cancers models was found to be sensible to the 249C cytotoxic agent with nanomolar potency [65]. V-ATPase subunit ATP6V1H was pointed out as a 249C drug target, provoking inhibition of its biochemical activity, lysosomal acidification, and macropinocytosis.

2.4. PPT1 Inhibitors

PPT1 is an enzyme responsible for protein depalmitoylation, regulating autophagy. PPT1 is a mobile depalmitoylating enzyme responsible for the cleavage of thioester linkages in palmitoylated proteins, facilitating their degradation. The hydrolase was identified to account for the proper localization of V-ATPase components onto the lysosomal membrane [66,67]. Indeed, chemical PPT1 inhibition induces V-ATPase subunit V0a1 misrouting, which dysregulates lysosomal acidification and thereby the autophagy process. PPT1 expression is high in many cancer types [68]. PPT1-dependent depalmitoylation regulates intracellular trafficking of a considerable number of proteins including most of the autophagy [69] and MTOR proteins [70]. Therefore, the development of potent PPT1 inhibitors is of strong interest in cancer.
Didemnin B, a cyclic depsipeptide, exhibits a potent antiproliferative effect and immunosuppressive activity both in vitro and in vivo against a panel of human cancers at low dosages [71]. It was later found to selectively elicit massive apoptosis via the dual inhibition of eukaryotic translation elongation factor 1 alpha 1 (EEF1A1) and PPT1 [72]. The marine natural product was the first to enter clinical development in the U.S. in cancer indication [73,74]. A phase 1 study led in Europe revealed that muscle toxicity was dose-limiting while the addition of carnitine allowed dosage escalation [75]. In 2018, Didemnin B obtained marketing authorization approval in the Asia–Pacific region for the treatment of multiple myeloma [76].
Chloroquine (CQ) and hydroxychloroquine (HCQ) antimalaria compounds are preferentially localized in lysosomal compartments due to their physicochemical properties [77,78]. Both drugs then provoke lysosomal compartment deacidification, stopping lysosomal enzyme activity, leading to autophagic flux inhibition and disruption of autophagosome–lysosome fusion [79]. HCQ was developed in response to the unexpected adverse effects of CQ treatment, such as severe constipation, gastrointestinal toxicity, cardiomyopathy, grade 3 fatigue, anemia, or retinal toxicity, all monitored in various cancer types [80,81,82,83]. HCQ anticancer drug effect evaluation during clinical trials revealed mixed results, exhibiting a partial [80,84,85] or insufficient antitumoral response compared to the standard of care [86,87,88]. Both CQ and HCQ autophagy inhibitors have nevertheless reached phase 4 clinical trials whilst never obtaining market approval for cancer indication. Nevertheless, their extensive investigation paves the road to the design and development of new potent autophagy inhibitors.
Amaravadi worked on Lys05, a bivalent form of HCQ [89], with it having more potent antitumor activity both in vitro and in vivo than HCQ as a single agent in multiple human cancer cell lines and xenograft models [90]. Following the idea of autophagy and MTORC1 regulators, they also studied DQ661. The group published two papers where they identified PPT1 as a target of DQ661, HCQ, and Lys05, while the molecular target of these drugs was unknown at that point [28,67].
GNS561, a lysosomotropic small molecule that modulates the autophagy process presents strong anticancer activity in a wide panel of cancers with preferential accumulation and efficacy in the liver [29]. Once located in lysosomal compartments, the molecule alters the structural and functional integrity of lysosomes, blocking the late stage of the autophagy process. The compound binds to PPT1 and reduces not only its enzymatic activity but its expression as well. GNS561 successfully completed a phase 1b trial in patients with primary and secondary liver cancer, highlighting the safety of the molecule [91]. GNS561 is now entering a phase 2 clinical trial in association with standard-of-care atezolizumab–bevacizumab as a first-line treatment in patients suffering from unresectable hepatocellular carcinoma (NCT05448677) (Table 1).

3. Rational of the Combination of Autophagy Inhibitors with Immune Checkpoint Inhibitors

3.1. The Immune System and Autophagy

Tumor cells continually interplay with their microenvironment which consists of cellular and non-cellular components [92] (Figure 3). The tumor microenvironment (TME) is of critical importance in tumor initiation, progression, metastasis, and resistance to treatment [93]. It further plays a significant role in tumor immune surveillance and immunological evasion [94,95,96,97]. Immune cells within the TME, encompassing CD8+ and CD4+ T cells, regulatory T lymphocytes, B cells, neutrophils, tumor-associated macrophages (TAMs), natural killer (NK) cells, and dendritic (DC) cells, decisively take part in this process.
As malignant cells, they display a diversity of relevant markers on their surfaces along with immune checkpoint molecules, essential for self-tolerance and immune response, enabling tumor suppression. However, interactions between some cancer cell-surface proteins with specific checkpoint proteins expressed on immune cells allow evasion from immune system anti-tumoral offensive [98,99]. Immune elimination failure mainly occurs through the disruption of two processes: (1) interaction between the major histocompatibility complex (MHC) on the surface of antigen-presenting cells (APCs), such as cancer cells and the T cell receptor (TCR), and (2) signalization displayed by antigen-independent co-signalling molecules, intimately regulated by co-stimulators or co-inhibitors known as immune checkpoints [100,101,102]. Downregulation of major histocompatibility complex class I (MHC-I) presentation has been observed in many different types of cancers [103,104,105,106,107] and is associated with poor prognosis. In addition, recognition of cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) and PD-1 co-inhibitory receptors, found on the surface of cytotoxic T cells (CTLs), with their tumor cell surface partner proteins B7-1/B7-2 and PD-L1, respectively, causes a lack of suitable T cell priming and activation, putting brakes on unrestricted cytotoxic T effector function against malignant cells [108,109,110].
ICIs, able to hamper the ‘off’ signal between cancer cells and T cells, have rapidly surfaced as a promising therapeutic option for cancer patients in the recent decades and have consequently been developed [111,112,113,114,115]. The ones targeting CTLA-4 (ipilimumab), PD-1 (pembrolizumab, nivolumab, and cemiplimab), and its partner protein PD-L1 (atezolizumab, avelumab, durvalumab), are currently approved and used in more than 50 cancer types, administered either alone or in combination with chemotherapies or even between them, as first or second lines [116,117].
There is growing evidence showing that autophagy signalling coordinates the immune response [118,119,120,121]. Working on a pancreatic cancer model, a paper demonstrated that autophagy participates in immune evasion through the selective targeting of MHC-I molecules for degradation [34]. Molecules are selectively addressed in an autophagy-dependent mechanism experiencing lysosomal degradation through the NBR1 autophagy cargo receptor. Decreased presentation of the molecules on cancer cells’ surface leads to obstructed antigen presentation and T cells’ cytotoxic activity. Conditional whole-body Atg7-deficient mice implanted with liver cancer with a high tumor mutational burden in a study pointed out reduced intratumoral T cell exhaustion [122]. Deficiency of HIP1R in tumor cells was demonstrated to cause PD-L1 accumulation and suppressed T-cell-mediated cytotoxicity [123]. HIP1R actually targets PD-L1 for lysosomal degradation, inhibiting tumor growth by increasing T cell cytotoxicity. The results suggest that selective autophagic degradation of PD-L1 avoids cancer immune escape. However, PD-L1 palmitoylation decreases its endosomal-sorting-mediated autophagic degradation, highlighting PPT1 as an interesting autophagy-related target to control immune evasion [124]. In addition, Amaravadi Laboratory observed clear enhancement of T cell priming with PPT1 inhibition but not with genetic inhibition of upstream autophagy genes [30]. They further showed that PPT1 inhibition leads to IFN-β release from macrophages, essential for T-cell-mediated killing and conducted M2 to M1 phenotype switching in macrophages. The autophagy inhibitor CQ was also established to be able to reset TAMs from M2 to the tumor-killing M1 phenotype modulating antitumor immune response [125]. Autophagy thus promotes tumor growth by inhibiting T cell immune response. In addition, there is evidence that autophagy inhibition in NK and DC promotes their functions in the TME, increasing infiltration and cytotoxicity [126,127]. Proficient autophagy in cancer-associated fibroblasts (CAFs) was moreover shown to participate in tumor growth [127] and boost metastasis via interleukin-6 secretion and NFκB signalling [128]. In brief, autophagy inhibition could impact antigen presentation and phenotype repolarization, promoting immune cells’ anticancer response. Therefore, the therapeutic potential of autophagy modulators for controlling immunity has recently been considered.

3.2. Autophagy Combinatorial Strategy with Immune Modulators

Despite ICIs’ massive and rapid approval in cancer indication due to their improved risk:benefit ratio over the former standard-of-care treatment, it is worthy of note that the already completed clinical trials were more or less successful, sometimes exhibiting moderate or disappointing clinical results regarding certain types and subtypes of cancer when ICIs are administered in monotherapy [129,130,131,132,133]. Patient response rates rarely reached and exceeded 40%, which is not only negligible but insufficient [134]. ICI combination itself was further shown to expose the exacerbated severity of immune-related adverse events in some cancer patients [135]. Because accumulating evidence suggests that a lower proportion of cancer patients benefit from conducive ICIs’ anti-tumoral effect than predicted, a combinatorial strategy with autophagy inhibitors in order to reinforce and optimize their efficacy is being presently studied.
Non-small-cell lung cancer (NSLC) patients with inactivating mutations in liver kinase B1 (LKB1) show poor response to anti-PD-1 immunotherapy [136]. Interestingly, Deng et al. recently demonstrated that LKB1 loss suppresses antigen processing and presentation to MHC because of the increased autophagic flux and compromised proteasomal degradation activity of antigenic peptides. ULK1 inhibition (MRT68921) or lysosomal function impairment (CQ) blocked the autophagic degradation of immunoproteasome constituents, successfully restoring antigen presentation and leading to increased T cell infiltration and improving the response to anti-PD-1 treatment in an LKB1 mutant NSCLC mouse model. The Yamamoto team demonstrated in vitro that tumor-specific autophagy inhibition using CQ drives increased MHC antigen presentation in a pancreatic ductal adenocarcinoma (PDAC) model, enhancing CD8+ T cell proliferation, activation, and tumor cell killing [34]. They first pointed out that CQ monotherapy failed to significantly lower tumor weight or enhance T cell infiltration in mice bearing orthotopic PDAC tumor while working with in combination with anti-PD-1 and anti-CTLA4; synergistic and potent anti-tumor activity as well as an increased anti-tumor immune response were registered. Amaravadi et al. reported that HCQ in combination with anti-PD-1 resulted in tumor growth attenuation and raised survival in melanoma mouse models [30]. Chemical PPT1 inhibition led to macrophages’ repolarization from M2 to the M1 phenotype and augmented T-cell-mediated cytotoxicity. They further observed a significant diminution in myeloid-derived suppressor cell infiltration in the TME. PPT1-deficient DCs were observed to enhance the priming of naive CD8+ T cells during viral immune response, suggesting enhanced DC function in the TME following autophagy inhibition [127]. Recently, the GNS561 PPT1 inhibitor combined with anti-PD-1 was highlighted as an attractive approach to restore immune response in a transgenic immunocompetent hepatocarcinoma (HCC) mouse model [137]. MHC-I cancer cells surface expression increased and led to cytotoxic T cells’ recolonization in the tumor site. A phase 2 study evaluating GNS561 combination with atezolizumab plus bevacizumab is currently recruiting for the first-line treatment of unresectable HCC patients (NCT05448677), with it being the first trial to assess the benefits of the autophagy PPT1 inhibitor with immune therapy. Recent studies have therefore pointed out that autophagy inhibitors combined with ICIs could work together to not only significantly reduce cytotoxic T cell exhaustion but also reset TAMs from M2 to the M1 phenotype, with them being an attractive therapeutic strategy to fight cancer. Autophagy inhibitors may thus partially rub out ICIs’ lack of effectiveness and resistance, improving antigen presentation and resetting the anti-tumoral immune cell profile. However, this novel combination regimen needs to be further assessed in preclinical studies and, more importantly, needs to be followed by clinical evaluation.

4. Concluding Remarks and Future Perspectives

Targeting the autophagy process to fight cancer is a promising strategy, especially in the framework of combination. A broad range of developed autophagy inhibitors have shown encouraging preclinical results with no or low toxicity issues and with powerful anticancerous activity in the nanomolar/micromolar range. Clinical translations have nevertheless been unsuccessful, demonstrating worrisome adverse events and insufficient efficacy. Indeed, almost none of the evaluated compounds were initially designed to precisely target autophagy before being investigated in cancer indication. Some fresh, more potent and specific candidates have entered recently preclinical and clinical research programs with results expected in the upcoming years. Recent publications emphasise their potency in combination with single or dual ICI therapy since their synergistic activity is able to remobilize the cytotoxic effect of CTLs and repolarize TAMs. Currently, only the new GNS561 autophagy inhibitor in combination with atezolizumab plus bevacizumab has been evaluated in a phase 2 cancer clinical trial. MEKi, such as ICIs, have shown encouraging preclinical results, but they curiously provided insufficient-to-no clinical benefits [138]. Inhibition of KRAS-RAF-MEK-ERK signalling displayed autophagy promotion, protecting cancer cells from the cytotoxic effects of KRAS pathway inhibition [33]. Interestingly, DCC-3116 was found to inhibit MAPK inhibitor-mediated compensatory increased autophagy and to enhance the anti-tumoral activity of trametinib in vitro [50]. DCC-3116, as monotherapy and in combination with trametinib, binimetinib, or sotorasib, is currently under phase 1/2 clinical trials in patients with advanced or metastatic solid tumors exhibiting MAPK pathway mutation (NCT04892017). Although targeting autophagy in cancer patients is a former idea and its achievement is still at a very early stage, combination with targeted therapy and MEKi is of major interest.
A recent examination of the literature spotlights possible new autophagy regulators as targets for new drug development. Comprehension of autophagosome biogenesis has taken a step forward since TMEM41B-deficiency was identified as being responsible for paralyzed autophagy initiation and lipid mobilization [139,140]. ATG9A and ATG2A have also recently been revealed to be crucial for autophagosome formation during the elongation period [141]. The phosphorylation status of VTI1B by PTPN9 [142] and that of syntaxin 17 by TANK-binding kinase 1 (TBK1) [143] was reported to be decisive for not only the expansion of phagophore structures and early autophagosome formation but as well for assembly of the ULK1 complex controlling the formation of phagophore structures, respectively. Klionsky and colleagues recently presented evidence that ATG14 is not only necessary to ULK1 complex initiation but that is also regulates autophagosome–lysosome fusion [144]. Moreover, they provide key elements showing that autophagy-related protein isoforms can dissimilarly impact core autophagy machinery. Exploration of the targeted protein degradation pathway may also turn out to be a powerful tool to move forward unanswered questions that have until now dampened the development of novel autophagy inhibitors. Targeted protein degradation strategies started with the emergence of a class of small pharmacological agents called proteolysis-targeting chimeras (PROTACs) [145]. This technology enables one to examine targets that were previously considered undruggable and offers a reversible effect [146]. The technology further provides resilience to acquired mutations, enhanced selectivity, and lower dosing requirements [147]. Preclinical campaigns and early clinical development have been launched, with the first clinical proof-of-concept surfacing in 2020 against two well-established cancer targets, the oestrogen receptor (ER) (ARV-471) and the androgen receptor (AR) (ARV-110). PROTACs also have the potential to be first-in-class small-molecule drugs that target immune cell activation [148,149]. However, there is still some work to be carried out regarding PROTAC design as their high molecular weight potentially limits not only cell permeability but pharmacokinetics evaluations as well.

Author Contributions

E.B. performed the literature review, wrote the initial draft, and completed subsequent edits. S.M. and P.H. contributed to the conceptualization and design of the work. E.R., S.M. and P.H. substantively revised it. Manuscript proofreading was carried out by E.R., S.M. and P.H., E.R. provided clinical expertise. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

Not applicable.

Conflicts of Interest

The authors are employees of Genoscience Pharma.

References

  1. Wang, L.; Ye, X.; Zhao, T. The Physiological Roles of Autophagy in the Mammalian Life Cycle. Biol. Rev. 2019, 94, 503–516. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  2. Jing, K.; Lim, K. Why Is Autophagy Important in Human Diseases? Exp. Mol. Med. 2012, 44, 69–72. [Google Scholar] [CrossRef] [Green Version]
  3. Fimia, G.M.; Stoykova, A.; Romagnoli, A.; Giunta, L.; Di Bartolomeo, S.; Nardacci, R.; Corazzari, M.; Fuoco, C.; Ucar, A.; Schwartz, P.; et al. Ambra1 Regulates Autophagy and Development of the Nervous System. Nature 2007, 447, 1121–1125. [Google Scholar] [CrossRef] [Green Version]
  4. Yue, Z.; Jin, S.; Yang, C.; Levine, A.J.; Heintz, N. Beclin 1, an Autophagy Gene Essential for Early Embryonic Development, Is a Haploinsufficient Tumor Suppressor. Proc. Natl. Acad. Sci. USA 2003, 100, 15077–15082. [Google Scholar] [CrossRef] [Green Version]
  5. Mathew, R.; Karantza-Wadsworth, V.; White, E. Role of Autophagy in Cancer. Nat. Rev. Cancer 2007, 7, 961–967. [Google Scholar] [CrossRef] [PubMed]
  6. White, E. The Role for Autophagy in Cancer. J. Clin. Investig. 2015, 125, 42–46. [Google Scholar] [CrossRef] [Green Version]
  7. Klionsky, D.J.; Petroni, G.; Amaravadi, R.K.; Baehrecke, E.H.; Ballabio, A.; Boya, P.; Bravo-San Pedro, J.M.; Cadwell, K.; Cecconi, F.; Choi, A.M.K.; et al. Autophagy in Major Human Diseases. EMBO J. 2021, 40, e108863. [Google Scholar] [CrossRef]
  8. Levine, B. Cell Biology: Autophagy and Cancer. Nature 2007, 446, 745–747. [Google Scholar] [CrossRef] [PubMed]
  9. Espert, L.; Denizot, M.; Grimaldi, M.; Robert-Hebmann, V.; Gay, B.; Varbanov, M.; Codogno, P.; Biard-Piechaczyk, M. Autophagy Is Involved in T Cell Death after Binding of HIV-1 Envelope Proteins to CXCR4. J. Clin. Investig. 2006, 116, 2161–2172. [Google Scholar] [CrossRef] [PubMed]
  10. Martinez-Vicente, M.; Cuervo, A.M. Autophagy and Neurodegeneration: When the Cleaning Crew Goes on Strike. Lancet Neurol. 2007, 6, 352–361. [Google Scholar] [CrossRef]
  11. Gunn, J.M.; Clark, M.G.; Knowles, S.E.; Hopgood, M.F.; Ballard, F.J. Reduced Rates of Proteolysis in Transformed Cells. Nature 1977, 266, 58–60. [Google Scholar] [CrossRef]
  12. Kisen, G.O.; Tessitore, L.; Costelli, P.; Gordon, P.B.; Schwarze, P.E.; Baccino, F.M.; Seglen, P.O. Reduced Autophagic Activity in Primary Rat Hepatocellular Carcinoma and Ascites Hepatoma Cells. Carcinogenesis 1993, 14, 2501–2505. [Google Scholar] [CrossRef] [PubMed]
  13. Yun, C.W.; Lee, S.H. The Roles of Autophagy in Cancer. Int. J. Mol. Sci. 2018, 19, 3466. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  14. White, E.; Mehnert, J.M.; Chan, C.S. Autophagy, Metabolism, and Cancer. Clin. Cancer Res. 2015, 21, 5037–5046. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Mukhopadhyay, S.; Biancur, D.E.; Parker, S.J.; Yamamoto, K.; Banh, R.S.; Paulo, J.A.; Mancias, J.D.; Kimmelman, A.C. Autophagy Is Required for Proper Cysteine Homeostasis in Pancreatic Cancer through Regulation of SLC7A11. Proc. Natl. Acad. Sci. USA 2021, 118, e2021475118. [Google Scholar] [CrossRef]
  16. Singh, S.S.; Vats, S.; Chia, A.Y.-Q.; Tan, T.Z.; Deng, S.; Ong, M.S.; Arfuso, F.; Yap, C.T.; Goh, B.C.; Sethi, G.; et al. Dual Role of Autophagy in Hallmarks of Cancer. Oncogene 2018, 37, 1142–1158. [Google Scholar] [CrossRef]
  17. Santana-Codina, N.; Mancias, J.D.; Kimmelman, A.C. The Role of Autophagy in Cancer. Annu. Rev. Cancer Biol. 2017, 1, 19–39. [Google Scholar] [CrossRef]
  18. Imlay, J.A.; Linn, S. DNA Damage and Oxygen Radical Toxicity. Science 1988, 240, 1302–1309. [Google Scholar] [CrossRef] [Green Version]
  19. Lazova, R.; Camp, R.L.; Klump, V.; Siddiqui, S.F.; Amaravadi, R.K.; Pawelek, J.M. Punctate LC3B Expression Is a Common Feature of Solid Tumors and Associated with Proliferation, Metastasis and Poor Outcome. Clin. Cancer Res. 2012, 18, 370–379. [Google Scholar] [CrossRef] [Green Version]
  20. Folkerts, H.; Hilgendorf, S.; Wierenga, A.T.J.; Jaques, J.; Mulder, A.B.; Coffer, P.J.; Schuringa, J.J.; Vellenga, E. Inhibition of Autophagy as a Treatment Strategy for P53 Wild-Type Acute Myeloid Leukemia. Cell Death Dis. 2017, 8, 2927. [Google Scholar] [CrossRef] [Green Version]
  21. Valastyan, S.; Weinberg, R.A. Tumor Metastasis: Molecular Insights and Evolving Paradigms. Cell 2011, 147, 275–292. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. White, E. Deconvoluting the Context-Dependent Role for Autophagy in Cancer. Nat. Rev. Cancer 2012, 12, 401–410. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Minamoto, T.; Nakayama, K.; Nakamura, K.; Katagiri, H.; Sultana, R.; Ishibashi, T.; Ishikawa, M.; Yamashita, H.; Sanuki, K.; Iida, K.; et al. Loss of Beclin 1 Expression in Ovarian Cancer: A Potential Biomarker for Predicting Unfavorable Outcomes. Oncol. Lett. 2018, 15, 1170–1176. [Google Scholar] [CrossRef] [Green Version]
  24. Qu, X.; Yu, J.; Bhagat, G.; Furuya, N.; Hibshoosh, H.; Troxel, A.; Rosen, J.; Eskelinen, E.-L.; Mizushima, N.; Ohsumi, Y.; et al. Promotion of Tumorigenesis by Heterozygous Disruption of the Beclin 1 Autophagy Gene. J. Clin. Investig. 2003, 112, 1809–1820. [Google Scholar] [CrossRef] [Green Version]
  25. Wijshake, T.; Zou, Z.; Chen, B.; Zhong, L.; Xiao, G.; Xie, Y.; Doench, J.G.; Bennett, L.; Levine, B. Tumor-Suppressor Function of Beclin 1 in Breast Cancer Cells Requires E-Cadherin. Proc. Natl. Acad. Sci. USA 2021, 118, e2020478118. [Google Scholar] [CrossRef]
  26. Takamura, A.; Komatsu, M.; Hara, T.; Sakamoto, A.; Kishi, C.; Waguri, S.; Eishi, Y.; Hino, O.; Tanaka, K.; Mizushima, N. Autophagy-Deficient Mice Develop Multiple Liver Tumors. Genes Dev. 2011, 25, 795–800. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  27. Saito, T.; Ichimura, Y.; Taguchi, K.; Suzuki, T.; Mizushima, T.; Takagi, K.; Hirose, Y.; Nagahashi, M.; Iso, T.; Fukutomi, T.; et al. P62/Sqstm1 Promotes Malignancy of HCV-Positive Hepatocellular Carcinoma through Nrf2-Dependent Metabolic Reprogramming. Nat. Commun. 2016, 7, 12030. [Google Scholar] [CrossRef]
  28. Rebecca, V.W.; Nicastri, M.C.; Fennelly, C.; Chude, C.I.; Barber-Rotenberg, J.S.; Ronghe, A.; McAfee, Q.; McLaughlin, N.P.; Zhang, G.; Goldman, A.R.; et al. PPT1 Promotes Tumor Growth and Is the Molecular Target of Chloroquine Derivatives in Cancer. Cancer Discov. 2019, 9, 220–229. [Google Scholar] [CrossRef] [Green Version]
  29. Brun, S.; Bestion, E.; Raymond, E.; Bassissi, F.; Jilkova, Z.M.; Mezouar, S.; Rachid, M.; Novello, M.; Tracz, J.; Hamaï, A.; et al. GNS561, a Clinical-Stage PPT1 Inhibitor, Is Efficient against Hepatocellular Carcinoma via Modulation of Lysosomal Functions. Autophagy 2022, 18, 678–694. [Google Scholar] [CrossRef]
  30. Sharma, G.; Ojha, R.; Noguera-Ortega, E.; Rebecca, V.W.; Attanasio, J.; Liu, S.; Piao, S.; Lee, J.J.; Nicastri, M.C.; Harper, S.L.; et al. PPT1 Inhibition Enhances the Antitumor Activity of Anti–PD-1 Antibody in Melanoma. JCI Insight 2020, 5, e133225. [Google Scholar] [CrossRef]
  31. Du, Y.-X.; Mamun, A.A.; Lyu, A.-P.; Zhang, H.-J. Natural Compounds Targeting the Autophagy Pathway in the Treatment of Colorectal Cancer. Int. J. Mol. Sci. 2023, 24, 7310. [Google Scholar] [CrossRef] [PubMed]
  32. Dickson, I. Autophagy Inhibitor Combination Strategies for Pancreatic Cancer. Nat. Rev. Gastroenterol. Hepatol. 2019, 16, 262–263. [Google Scholar] [CrossRef] [PubMed]
  33. Kinsey, C.G.; Camolotto, S.A.; Boespflug, A.M.; Guillen, K.P.; Foth, M.; Truong, A.; Schuman, S.S.; Shea, J.E.; Seipp, M.T.; Yap, J.T.; et al. Protective Autophagy Elicited by RAF→MEK→ERK Inhibition Suggests a Treatment Strategy for RAS-Driven Cancers. Nat. Med. 2019, 25, 620–627. [Google Scholar] [CrossRef] [PubMed]
  34. Yamamoto, K.; Venida, A.; Yano, J.; Biancur, D.E.; Kakiuchi, M.; Gupta, S.; Sohn, A.S.W.; Mukhopadhyay, S.; Lin, E.Y.; Parker, S.J.; et al. Autophagy Promotes Immune Evasion of Pancreatic Cancer by Degrading MHC-I. Nature 2020, 581, 100–105. [Google Scholar] [CrossRef] [PubMed]
  35. Blommaart, E.F.; Krause, U.; Schellens, J.P.; Vreeling-Sindelárová, H.; Meijer, A.J. The Phosphatidylinositol 3-Kinase Inhibitors Wortmannin and LY294002 Inhibit Autophagy in Isolated Rat Hepatocytes. Eur. J. Biochem. 1997, 243, 240–246. [Google Scholar] [CrossRef] [Green Version]
  36. Seglen, P.O.; Gordon, P.B. 3-Methyladenine: Specific Inhibitor of Autophagic/Lysosomal Protein Degradation in Isolated Rat Hepatocytes. Proc. Natl. Acad. Sci. USA 1982, 79, 1889–1892. [Google Scholar] [CrossRef] [Green Version]
  37. Ronan, B.; Flamand, O.; Vescovi, L.; Dureuil, C.; Durand, L.; Fassy, F.; Bachelot, M.-F.; Lamberton, A.; Mathieu, M.; Bertrand, T.; et al. A Highly Potent and Selective Vps34 Inhibitor Alters Vesicle Trafficking and Autophagy. Nat. Chem. Biol. 2014, 10, 1013–1019. [Google Scholar] [CrossRef]
  38. Chen, S.; Wang, C.; Yeo, S.; Liang, C.-C.; Okamoto, T.; Sun, S.; Wen, J.; Guan, J.-L. Distinct Roles of Autophagy-Dependent and -Independent Functions of FIP200 Revealed by Generation and Analysis of a Mutant Knock-in Mouse Model. Genes Dev. 2016, 30, 856–869. [Google Scholar] [CrossRef] [Green Version]
  39. Hosokawa, N.; Hara, T.; Kaizuka, T.; Kishi, C.; Takamura, A.; Miura, Y.; Iemura, S.; Natsume, T.; Takehana, K.; Yamada, N.; et al. Nutrient-Dependent MTORC1 Association with the ULK1-Atg13-FIP200 Complex Required for Autophagy. Mol. Biol. Cell 2009, 20, 1981–1991. [Google Scholar] [CrossRef] [Green Version]
  40. Mercer, C.A.; Kaliappan, A.; Dennis, P.B. A Novel, Human Atg13 Binding Protein, Atg101, Interacts with ULK1 and Is Essential for Macroautophagy. Autophagy 2009, 5, 649–662. [Google Scholar] [CrossRef] [Green Version]
  41. Petherick, K.J.; Conway, O.J.L.; Mpamhanga, C.; Osborne, S.A.; Kamal, A.; Saxty, B.; Ganley, I.G. Pharmacological Inhibition of ULK1 Kinase Blocks Mammalian Target of Rapamycin (MTOR)-Dependent Autophagy. J. Biol. Chem. 2015, 290, 11376–11383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  42. Clark, K.; Peggie, M.; Plater, L.; Sorcek, R.J.; Young, E.R.R.; Madwed, J.B.; Hough, J.; McIver, E.G.; Cohen, P. Novel Cross-Talk within the IKK Family Controls Innate Immunity. Biochem. J. 2011, 434, 93–104. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  43. Tanida, I.; Minematsu-Ikeguchi, N.; Ueno, T.; Kominami, E. Lysosomal Turnover, but Not a Cellular Level, of Endogenous LC3 Is a Marker for Autophagy. Autophagy 2005, 1, 84–91. [Google Scholar] [CrossRef] [Green Version]
  44. Egan, D.F.; Chun, M.G.H.; Vamos, M.; Zou, H.; Rong, J.; Miller, C.J.; Lou, H.J.; Raveendra-Panickar, D.; Yang, C.-C.; Sheffler, D.J.; et al. Small Molecule Inhibition of the Autophagy Kinase ULK1 and Identification of ULK1 Substrates. Mol. Cell 2015, 59, 285–297. [Google Scholar] [CrossRef] [Green Version]
  45. Lu, J.; Zhu, L.; Zheng, L.-P.; Cui, Q.; Zhu, H.-H.; Zhao, H.; Shen, Z.-J.; Dong, H.-Y.; Chen, S.-S.; Wu, W.-Z.; et al. Overexpression of ULK1 Represents a Potential Diagnostic Marker for Clear Cell Renal Carcinoma and the Antitumor Effects of SBI-0206965. EBioMedicine 2018, 34, 85–93. [Google Scholar] [CrossRef] [Green Version]
  46. Dower, C.M.; Bhat, N.; Gebru, M.T.; Chen, L.; Wills, C.A.; Miller, B.A.; Wang, H.-G. Targeted Inhibition of ULK1 Promotes Apoptosis and Suppresses Tumor Growth and Metastasis in Neuroblastoma. Mol. Cancer Ther. 2018, 17, 2365–2376. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Tang, F.; Hu, P.; Yang, Z.; Xue, C.; Gong, J.; Sun, S.; Shi, L.; Zhang, S.; Li, Z.; Yang, C.; et al. SBI0206965, a Novel Inhibitor of Ulk1, Suppresses Non-Small Cell Lung Cancer Cell Growth by Modulating Both Autophagy and Apoptosis Pathways. Oncol. Rep. 2017, 37, 3449–3458. [Google Scholar] [CrossRef] [Green Version]
  48. Dite, T.A.; Langendorf, C.G.; Hoque, A.; Galic, S.; Rebello, R.J.; Ovens, A.J.; Lindqvist, L.M.; Ngoei, K.R.W.; Ling, N.X.Y.; Furic, L.; et al. AMP-Activated Protein Kinase Selectively Inhibited by the Type II Inhibitor SBI-0206965. J. Biol. Chem. 2018, 293, 8874–8885. [Google Scholar] [CrossRef] [Green Version]
  49. Martin, K.R.; Celano, S.L.; Solitro, A.R.; Gunaydin, H.; Scott, M.; O’Hagan, R.C.; Shumway, S.D.; Fuller, P.; MacKeigan, J.P. A Potent and Selective ULK1 Inhibitor Suppresses Autophagy and Sensitizes Cancer Cells to Nutrient Stress. iScience 2018, 8, 74–84. [Google Scholar] [CrossRef] [Green Version]
  50. Smith, B.D.; Vogeti, L.; Gupta, A.; Singh, J.; Al-Ani, G.; Bulfer, S.L.; Caldwell, T.M.; Timson, M.J.; Vogeti, S.; Ahn, Y.M.; et al. Abstract B129: Preclinical Studies with DCC-3116, an ULK Kinase Inhibitor Designed to Inhibit Autophagy as a Potential Strategy to Address Mutant RAS Cancers. Mol. Cancer Ther. 2019, 18, B129. [Google Scholar] [CrossRef]
  51. McMahon, M.; Bogdan, M.; Timson, M.J.; Al-Hashimi, H.; Ghazi, P.; Zhan, Y.; Smith, B.D.; Kinsey, C.G.; Flynn, D.L. Abstract 3600: DCC-3116, a First-in-Class Selective Inhibitor of ULK1/2 Kinases and Autophagy, Synergizes with the KRASG12C Inhibitor Sotorasib Resulting in Tumor Regression in KRAS Mutant NSCLC Xenograft Models. Cancer Res. 2022, 82, 3600. [Google Scholar] [CrossRef]
  52. Pasquier, B.; El-Ahmad, Y.; Filoche-Rommé, B.; Dureuil, C.; Fassy, F.; Abecassis, P.-Y.; Mathieu, M.; Bertrand, T.; Benard, T.; Barrière, C.; et al. Discovery of (2S)-8-[(3R)-3-Methylmorpholin-4-Yl]-1-(3-Methyl-2-Oxobutyl)-2-(Trifluoromethyl)-3,4-Dihydro-2H-Pyrimido[1,2-a]Pyrimidin-6-One: A Novel Potent and Selective Inhibitor of Vps34 for the Treatment of Solid Tumors. J. Med. Chem. 2015, 58, 376–400. [Google Scholar] [CrossRef] [PubMed]
  53. Malebari, A.M.; Abd Alhameed, R.; Almarhoon, Z.; Farooq, M.; Wadaan, M.A.M.; Sharma, A.; de la Torre, B.G.; Albericio, F.; El-Faham, A. The Antiproliferative and Apoptotic Effect of a Novel Synthesized S-Triazine Dipeptide Series, and Toxicity Screening in Zebrafish Embryos. Molecules 2021, 26, 1170. [Google Scholar] [CrossRef]
  54. Ge, C.; Chang, L.; Zhao, Y.; Chang, C.; Xu, X.; He, H.; Wang, Y.; Dai, F.; Xie, S.; Wang, C. Design, Synthesis and Evaluation of Naphthalimide Derivatives as Potential Anticancer Agents for Hepatocellular Carcinoma. Molecules 2017, 22, 342. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  55. Zhao, X.; Dong, W.; Gao, Y.; Shin, D.-S.; Ye, Q.; Su, L.; Jiang, F.; Zhao, B.; Miao, J. Novel Indolyl-Chalcone Derivatives Inhibit A549 Lung Cancer Cell Growth through Activating Nrf-2/HO-1 and Inducing Apoptosis in vitro and in vivo. Sci. Rep. 2017, 7, 3919. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Wei, J.; Liang, Y.; Wu, L. Design, Synthesis, Molecular Docking, and Tumor Resistance Reversal Activity Evaluation of Matrine Derivative with Thiophene Structure. Molecules 2021, 26, 417. [Google Scholar] [CrossRef]
  57. Demirayak, S.; Yurttas, L.; Gundogdu-Karaburun, N.; Karaburun, A.C.; Kayagil, I. Synthesis and Anti-Cancer Activity Evaluation of New Aurone Derivatives. J. Enzyme Inhib. Med. Chem. 2015, 30, 816–825. [Google Scholar] [CrossRef] [Green Version]
  58. Li, G.; Boyle, J.W.; Ko, C.-N.; Zeng, W.; Wong, V.K.W.; Wan, J.-B.; Chan, P.W.H.; Ma, D.-L.; Leung, C.-H. Aurone Derivatives as Vps34 Inhibitors That Modulate Autophagy. Acta Pharm. Sin. B 2019, 9, 537–544. [Google Scholar] [CrossRef]
  59. Dyczynski, M.; Yu, Y.; Otrocka, M.; Parpal, S.; Braga, T.; Henley, A.B.; Zazzi, H.; Lerner, M.; Wennerberg, K.; Viklund, J.; et al. Targeting Autophagy by Small Molecule Inhibitors of Vacuolar Protein Sorting 34 (Vps34) Improves the Sensitivity of Breast Cancer Cells to Sunitinib. Cancer Lett. 2018, 435, 32–43. [Google Scholar] [CrossRef]
  60. Noman, M.Z.; Parpal, S.; Van Moer, K.; Xiao, M.; Yu, Y.; Viklund, J.; De Milito, A.; Hasmim, M.; Andersson, M.; Amaravadi, R.K.; et al. Inhibition of Vps34 Reprograms Cold into Hot Inflamed Tumors and Improves Anti-PD-1/PD-L1 Immunotherapy. Sci. Adv. 2020, 6, eaax7881. [Google Scholar] [CrossRef] [PubMed]
  61. Pasquier, B. SAR405, a PIK3C3/Vps34 Inhibitor That Prevents Autophagy and Synergizes with MTOR Inhibition in Tumor Cells. Autophagy 2015, 11, 725–726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  62. Jaber, N.; Mohd-Naim, N.; Wang, Z.; DeLeon, J.L.; Kim, S.; Zhong, H.; Sheshadri, N.; Dou, Z.; Edinger, A.L.; Du, G.; et al. Vps34 Regulates Rab7 and Late Endocytic Trafficking through Recruitment of the GTPase-Activating Protein Armus. J. Cell. Sci. 2016, 129, 4424–4435. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Mauvezin, C.; Neufeld, T.P. Bafilomycin A1 Disrupts Autophagic Flux by Inhibiting Both V-ATPase-Dependent Acidification and Ca-P60A/SERCA-Dependent Autophagosome-Lysosome Fusion. Autophagy 2015, 11, 1437–1438. [Google Scholar] [CrossRef] [Green Version]
  64. Seguin, S.J.; Morelli, F.F.; Vinet, J.; Amore, D.; De Biasi, S.; Poletti, A.; Rubinsztein, D.C.; Carra, S. Inhibition of Autophagy, Lysosome and VCP Function Impairs Stress Granule Assembly. Cell. Death Differ. 2014, 21, 1838–1851. [Google Scholar] [CrossRef] [Green Version]
  65. Tolani, B.; Celli, A.; Yao, Y.; Tan, Y.Z.; Fetter, R.; Liem, C.R.; de Smith, A.J.; Vasanthakumar, T.; Bisignano, P.; Cotton, A.D.; et al. Ras-Mutant Cancers Are Sensitive to Small Molecule Inhibition of V-Type ATPases in Mice. Nat. Biotechnol. 2022, 40, 1834–1844. [Google Scholar] [CrossRef] [PubMed]
  66. Bagh, M.B.; Peng, S.; Chandra, G.; Zhang, Z.; Singh, S.P.; Pattabiraman, N.; Liu, A.; Mukherjee, A.B. Misrouting of V-ATPase Subunit V0a1 Dysregulates Lysosomal Acidification in a Neurodegenerative Lysosomal Storage Disease Model. Nat. Commun. 2017, 8, 14612. [Google Scholar] [CrossRef] [Green Version]
  67. Rebecca, V.W.; Nicastri, M.C.; McLaughlin, N.; Fennelly, C.; McAfee, Q.; Ronghe, A.; Nofal, M.; Lim, C.-Y.; Witze, E.; Chude, C.I.; et al. A Unified Approach to Targeting the Lysosome’s Degradative and Growth Signaling Roles. Cancer Discov. 2017, 7, 1266–1283. [Google Scholar] [CrossRef] [Green Version]
  68. Expression of PPT1 in Cancer-Summary-The Human Protein Atlas. Available online: https://www.proteinatlas.org/ENSG00000131238-PPT1/pathology (accessed on 1 August 2021).
  69. Koster, K.P.; Yoshii, A. Depalmitoylation by Palmitoyl-Protein Thioesterase 1 in Neuronal Health and Degeneration. Front. Synaptic Neurosci. 2019, 11, 25. [Google Scholar] [CrossRef] [Green Version]
  70. Sanders, S.S.; De Simone, F.I.; Thomas, G.M. MTORC1 Signaling Is Palmitoylation-Dependent in Hippocampal Neurons and Non-Neuronal Cells and Involves Dynamic Palmitoylation of LAMTOR1 and MTOR. Front. Cell. Neurosci. 2019, 13, 115. [Google Scholar] [CrossRef] [Green Version]
  71. Lee, J.; Currano, J.N.; Carroll, P.J.; Joullié, M.M. Didemnins, Tamandarins and Related Natural Products. Nat. Prod. Rep. 2012, 29, 404–424. [Google Scholar] [CrossRef]
  72. Potts, M.B.; McMillan, E.A.; Rosales, T.I.; Kim, H.S.; Ou, Y.-H.; Toombs, J.E.; Brekken, R.A.; Minden, M.D.; MacMillan, J.B.; White, M.A. Mode of Action and Pharmacogenomic Biomarkers for Exceptional Responders to Didemnin B. Nat. Chem. Biol. 2015, 11, 401–408. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  73. Le Tourneau, C.; Raymond, E.; Faivre, S. Aplidine: A Paradigm of How to Handle the Activity and Toxicity of a Novel Marine Anticancer Poison. Curr. Pharm. Des. 2007, 13, 3427–3439. [Google Scholar] [CrossRef]
  74. Vera, M.D.; Joullié, M.M. Natural Products as Probes of Cell Biology: 20 Years of Didemnin Research. Med. Res. Rev. 2002, 22, 102–145. [Google Scholar] [CrossRef]
  75. Faivre, S.; Chièze, S.; Delbaldo, C.; Ady-Vago, N.; Guzman, C.; Lopez-Lazaro, L.; Lozahic, S.; Jimeno, J.; Pico, F.; Armand, J.P.; et al. Phase I and Pharmacokinetic Study of Aplidine, a New Marine Cyclodepsipeptide in Patients with Advanced Malignancies. J. Clin. Oncol. Off. J. Am. Soc. Clin. Oncol. 2005, 23, 7871–7880. [Google Scholar] [CrossRef] [PubMed]
  76. Martinez-Cava, M. PharmaMar Announces the Approval of Aplidin® in Australia for the Treatment of Multiple Myeloma. Available online: https://pharmamar.com/wp-content/uploads/2021/11/11-12-2018-PharmaMar-announces-the-approval-of-Aplidin%C2%AE-in-Australia-for-the-treatment-of-multiple-myeloma.pdf (accessed on 10 June 2023).
  77. Cardelli, J.A.; Richardson, J.; Miears, D. Role of Acidic Intracellular Compartments in the Biosynthesis of Dictyostelium Lysosomal Enzymes. The Weak Bases Ammonium Chloride and Chloroquine Differentially Affect Proteolytic Processing and Sorting. J. Biol. Chem. 1989, 264, 3454–3463. [Google Scholar] [CrossRef]
  78. Zhitomirsky, B.; Assaraf, Y.G. Lysosomal Sequestration of Hydrophobic Weak Base Chemotherapeutics Triggers Lysosomal Biogenesis and Lysosome-Dependent Cancer Multidrug Resistance. Oncotarget 2014, 6, 1143–1156. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  79. Mauthe, M.; Orhon, I.; Rocchi, C.; Zhou, X.; Luhr, M.; Hijlkema, K.-J.; Coppes, R.P.; Engedal, N.; Mari, M.; Reggiori, F. Chloroquine Inhibits Autophagic Flux by Decreasing Autophagosome-Lysosome Fusion. Autophagy 2018, 14, 1435–1455. [Google Scholar] [CrossRef] [Green Version]
  80. Mahalingam, D.; Mita, M.; Sarantopoulos, J.; Wood, L.; Amaravadi, R.K.; Davis, L.E.; Mita, A.C.; Curiel, T.J.; Espitia, C.M.; Nawrocki, S.T.; et al. Combined Autophagy and HDAC Inhibition: A Phase I Safety, Tolerability, Pharmacokinetic, and Pharmacodynamic Analysis of Hydroxychloroquine in Combination with the HDAC Inhibitor Vorinostat in Patients with Advanced Solid Tumors. Autophagy 2014, 10, 1403–1414. [Google Scholar] [CrossRef] [Green Version]
  81. Browning, D.J. Pharmacology of Chloroquine and Hydroxychloroquine. In Hydroxychloroquine and Chloroquine Retinopathy; Browning, D.J., Ed.; Springer: New York, NY, USA, 2014; pp. 35–63. ISBN 978-1-4939-0597-3. [Google Scholar]
  82. Costedoat-Chalumeau, N.; Dunogué, B.; Leroux, G.; Morel, N.; Jallouli, M.; Le Guern, V.; Piette, J.-C.; Brézin, A.P.; Melles, R.B.; Marmor, M.F. A Critical Review of the Effects of Hydroxychloroquine and Chloroquine on the Eye. Clin. Rev. Allergy Immunol. 2015, 49, 317–326. [Google Scholar] [CrossRef]
  83. Costedoat-Chalumeau, N.; Hulot, J.-S.; Amoura, Z.; Delcourt, A.; Maisonobe, T.; Dorent, R.; Bonnet, N.; Sablé, R.; Lechat, P.; Wechsler, B.; et al. Cardiomyopathy Related to Antimalarial Therapy with Illustrative Case Report. Cardiology 2007, 107, 73–80. [Google Scholar] [CrossRef]
  84. Rangwala, R.; Chang, Y.C.; Hu, J.; Algazy, K.M.; Evans, T.L.; Fecher, L.A.; Schuchter, L.M.; Torigian, D.A.; Panosian, J.T.; Troxel, A.B.; et al. Combined MTOR and Autophagy Inhibition: Phase I Trial of Hydroxychloroquine and Temsirolimus in Patients with Advanced Solid Tumors and Melanoma. Autophagy 2014, 10, 1391–1402. [Google Scholar] [CrossRef] [PubMed]
  85. Vogl, D.T.; Stadtmauer, E.A.; Tan, K.-S.; Heitjan, D.F.; Davis, L.E.; Pontiggia, L.; Rangwala, R.; Piao, S.; Chang, Y.C.; Scott, E.C.; et al. Combined Autophagy and Proteasome Inhibition: A Phase 1 Trial of Hydroxychloroquine and Bortezomib in Patients with Relapsed/Refractory Myeloma. Autophagy 2014, 10, 1380–1390. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Stupp, R.; Mason, W.P.; van den Bent, M.J.; Weller, M.; Fisher, B.; Taphoorn, M.J.B.; Belanger, K.; Brandes, A.A.; Marosi, C.; Bogdahn, U.; et al. Radiotherapy plus Concomitant and Adjuvant Temozolomide for Glioblastoma. N. Engl. J. Med. 2005, 352, 987–996. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  87. Goldberg, S.B.; Supko, J.G.; Neal, J.W.; Muzikansky, A.; Digumarthy, S.; Fidias, P.; Temel, J.S.; Heist, R.S.; Shaw, A.T.; McCarthy, P.O.; et al. A Phase I Study of Erlotinib and Hydroxychloroquine in Advanced Non-Small-Cell Lung Cancer. J. Thorac. Oncol. 2012, 7, 1602–1608. [Google Scholar] [CrossRef] [Green Version]
  88. Wolpin, B.M.; Rubinson, D.A.; Wang, X.; Chan, J.A.; Cleary, J.M.; Enzinger, P.C.; Fuchs, C.S.; McCleary, N.J.; Meyerhardt, J.A.; Ng, K.; et al. Phase II and Pharmacodynamic Study of Autophagy Inhibition Using Hydroxychloroquine in Patients with Metastatic Pancreatic Adenocarcinoma. Oncologist 2014, 19, 637–638. [Google Scholar] [CrossRef] [Green Version]
  89. Amaravadi, R.K.; Winkler, J.D. Lys05: A New Lysosomal Autophagy Inhibitor. Autophagy 2012, 8, 1383–1384. [Google Scholar] [CrossRef] [Green Version]
  90. McAfee, Q.; Zhang, Z.; Samanta, A.; Levi, S.M.; Ma, X.-H.; Piao, S.; Lynch, J.P.; Uehara, T.; Sepulveda, A.R.; Davis, L.E.; et al. Autophagy Inhibitor Lys05 Has Single-Agent Antitumor Activity and Reproduces the Phenotype of a Genetic Autophagy Deficiency. Proc. Natl. Acad. Sci. USA 2012, 109, 8253–8258. [Google Scholar] [CrossRef] [Green Version]
  91. Harding, J.J.; Awada, A.; Roth, G.; Decaens, T.; Merle, P.; Kotecki, N.; Dreyer, C.; Ansaldi, C.; Rachid, M.; Mezouar, S.; et al. First-In-Human Effects of PPT1 Inhibition Using the Oral Treatment with GNS561/Ezurpimtrostat in Patients with Primary and Secondary Liver Cancers. Liver Cancer 2022, 11, 268–277. [Google Scholar] [CrossRef] [PubMed]
  92. Fridman, W.H.; Pagès, F.; Sautès-Fridman, C.; Galon, J. The Immune Contexture in Human Tumours: Impact on Clinical Outcome. Nat. Rev. Cancer 2012, 12, 298–306. [Google Scholar] [CrossRef]
  93. Carreras, J.; Kikuti, Y.Y.; Miyaoka, M.; Hiraiwa, S.; Tomita, S.; Ikoma, H.; Kondo, Y.; Ito, A.; Nakamura, N.; Hamoudi, R. A Combination of Multilayer Perceptron, Radial Basis Function Artificial Neural Networks and Machine Learning Image Segmentation for the Dimension Reduction and the Prognosis Assessment of Diffuse Large B-Cell Lymphoma. AI 2021, 2, 106–134. [Google Scholar] [CrossRef]
  94. Tang, T.; Huang, X.; Zhang, G.; Hong, Z.; Bai, X.; Liang, T. Advantages of Targeting the Tumor Immune Microenvironment over Blocking Immune Checkpoint in Cancer Immunotherapy. Sig. Transduct. Target. Ther. 2021, 6, 72. [Google Scholar] [CrossRef] [PubMed]
  95. Binnewies, M.; Roberts, E.W.; Kersten, K.; Chan, V.; Fearon, D.F.; Merad, M.; Coussens, L.M.; Gabrilovich, D.I.; Ostrand-Rosenberg, S.; Hedrick, C.C.; et al. Understanding the Tumor Immune Microenvironment (TIME) for Effective Therapy. Nat. Med. 2018, 24, 541–550. [Google Scholar] [CrossRef] [PubMed]
  96. Zhang, Y.; Chen, L. Classification of Advanced Human Cancers Based on Tumor Immunity in the MicroEnvironment (TIME) for Cancer Immunotherapy. JAMA Oncol. 2016, 2, 1403–1404. [Google Scholar] [CrossRef] [PubMed]
  97. Petitprez, F.; Meylan, M.; de Reyniès, A.; Sautès-Fridman, C.; Fridman, W.H. The Tumor Microenvironment in the Response to Immune Checkpoint Blockade Therapies. Front. Immunol. 2020, 11, 784. [Google Scholar] [CrossRef]
  98. Yoshihama, S.; Roszik, J.; Downs, I.; Meissner, T.B.; Vijayan, S.; Chapuy, B.; Sidiq, T.; Shipp, M.A.; Lizee, G.A.; Kobayashi, K.S. NLRC5/MHC Class I Transactivator Is a Target for Immune Evasion in Cancer. Proc. Natl. Acad. Sci. USA 2016, 113, 5999–6004. [Google Scholar] [CrossRef] [Green Version]
  99. Mojic, M.; Takeda, K.; Hayakawa, Y. The Dark Side of IFN-γ: Its Role in Promoting Cancer Immunoevasion. Int. J. Mol. Sci. 2017, 19, 89. [Google Scholar] [CrossRef] [Green Version]
  100. Khong, H.T.; Restifo, N.P. Natural Selection of Tumor Variants in the Generation of “Tumor Escape” Phenotypes. Nat. Immunol. 2002, 3, 999–1005. [Google Scholar] [CrossRef] [Green Version]
  101. Rabinovich, G.A.; Gabrilovich, D.; Sotomayor, E.M. Immunosuppressive Strategies That Are Mediated by Tumor Cells. Annu. Rev. Immunol. 2007, 25, 267–296. [Google Scholar] [CrossRef] [Green Version]
  102. Suresh, S.; O’Donnell, K.A. Translational Control of Immune Evasion in Cancer. Trends Cancer 2021, 7, 580–582. [Google Scholar] [CrossRef]
  103. Watson, N.F.S.; Ramage, J.M.; Madjd, Z.; Spendlove, I.; Ellis, I.O.; Scholefield, J.H.; Durrant, L.G. Immunosurveillance Is Active in Colorectal Cancer as Downregulation but Not Complete Loss of MHC Class I Expression Correlates with a Poor Prognosis. Int. J. Cancer 2006, 118, 6–10. [Google Scholar] [CrossRef]
  104. Palmisano, G.L.; Pistillo, M.P.; Capanni, P.; Pera, C.; Nicolò, G.; Salvi, S.; Perdelli, L.; Pasciucco, G.; Ferrara, G.B. Investigation of HLA Class I Downregulation in Breast Cancer by RT-PCR. Hum. Immunol. 2001, 62, 133–139. [Google Scholar] [CrossRef] [PubMed]
  105. Spel, L.; Boelens, J.-J.; van der Steen, D.M.; Blokland, N.J.G.; van Noesel, M.M.; Molenaar, J.J.; Heemskerk, M.H.M.; Boes, M.; Nierkens, S. Natural Killer Cells Facilitate PRAME-Specific T-Cell Reactivity against Neuroblastoma. Oncotarget 2015, 6, 35770–35781. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  106. Meissner, M.; Reichert, T.E.; Kunkel, M.; Gooding, W.; Whiteside, T.L.; Ferrone, S.; Seliger, B. Defects in the Human Leukocyte Antigen Class I Antigen Processing Machinery in Head and Neck Squamous Cell Carcinoma: Association with Clinical Outcome. Clin. Cancer Res. 2005, 11, 2552–2560. [Google Scholar] [CrossRef] [Green Version]
  107. Romero, J.M.; Jiménez, P.; Cabrera, T.; Cózar, J.M.; Pedrinaci, S.; Tallada, M.; Garrido, F.; Ruiz-Cabello, F. Coordinated Downregulation of the Antigen Presentation Machinery and HLA Class I/Beta2-Microglobulin Complex Is Responsible for HLA-ABC Loss in Bladder Cancer. Int. J. Cancer 2005, 113, 605–610. [Google Scholar] [CrossRef] [PubMed]
  108. Chen, D.S.; Mellman, I. Elements of Cancer Immunity and the Cancer-Immune Set Point. Nature 2017, 541, 321–330. [Google Scholar] [CrossRef]
  109. Wolchok, J. Putting the Immunologic Brakes on Cancer. Cell 2018, 175, 1452–1454. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  110. O’Reilly, E.M.; Oh, D.-Y.; Dhani, N.; Renouf, D.J.; Lee, M.A.; Sun, W.; Fisher, G.; Hezel, A.; Chang, S.-C.; Vlahovic, G.; et al. Durvalumab with or without Tremelimumab for Patients with Metastatic Pancreatic Ductal Adenocarcinoma: A Phase 2 Randomized Clinical Trial. JAMA Oncol. 2019, 5, 1431–1438. [Google Scholar] [CrossRef]
  111. Xiao, Y.; Yu, D. Tumor Microenvironment as a Therapeutic Target in Cancer. Pharmacol. Ther. 2021, 221, 107753. [Google Scholar] [CrossRef]
  112. Baghban, R.; Roshangar, L.; Jahanban-Esfahlan, R.; Seidi, K.; Ebrahimi-Kalan, A.; Jaymand, M.; Kolahian, S.; Javaheri, T.; Zare, P. Tumor Microenvironment Complexity and Therapeutic Implications at a Glance. Cell Commun. Signal. 2020, 18, 59. [Google Scholar] [CrossRef] [Green Version]
  113. Immune Checkpoint Inhibitors-NCI. Available online: https://www.cancer.gov/about-cancer/treatment/types/immunotherapy/checkpoint-inhibitors (accessed on 19 May 2023).
  114. Vinay, D.S.; Ryan, E.P.; Pawelec, G.; Talib, W.H.; Stagg, J.; Elkord, E.; Lichtor, T.; Decker, W.K.; Whelan, R.L.; Kumara, H.M.C.S.; et al. Immune Evasion in Cancer: Mechanistic Basis and Therapeutic Strategies. Semin. Cancer Biol. 2015, 35, S185–S198. [Google Scholar] [CrossRef]
  115. Duan, Z.; Luo, Y. Targeting Macrophages in Cancer Immunotherapy. Sig. Transduct. Target. Ther. 2021, 6, 127. [Google Scholar] [CrossRef]
  116. Robert, C. A Decade of Immune-Checkpoint Inhibitors in Cancer Therapy. Nat. Commun. 2020, 11, 3801. [Google Scholar] [CrossRef]
  117. Immune Checkpoint Inhibitors and Their Side Effects. Available online: https://www.cancer.org/cancer/managing-cancer/treatment-types/immunotherapy/immune-checkpoint-inhibitors.html (accessed on 19 May 2023).
  118. Jang, Y.J.; Kim, J.H.; Byun, S. Modulation of Autophagy for Controlling Immunity. Cells 2019, 8, 138. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  119. Maes, H.; Rubio, N.; Garg, A.D.; Agostinis, P. Autophagy: Shaping the Tumor Microenvironment and Therapeutic Response. Trends Mol. Med. 2013, 19, 428–446. [Google Scholar] [CrossRef]
  120. Amaravadi, R.K.; Lippincott-Schwartz, J.; Yin, X.-M.; Weiss, W.A.; Takebe, N.; Timmer, W.; DiPaola, R.S.; Lotze, M.T.; White, E. Principles and Current Strategies for Targeting Autophagy for Cancer Treatment. Clin. Cancer Res. 2011, 17, 654–666. [Google Scholar] [CrossRef] [Green Version]
  121. Liang, X.; De Vera, M.E.; Buchser, W.J.; Romo de Vivar Chavez, A.; Loughran, P.; Beer Stolz, D.; Basse, P.; Wang, T.; Van Houten, B.; Zeh, H.J.; et al. Inhibiting Systemic Autophagy during Interleukin 2 Immunotherapy Promotes Long-Term Tumor Regression. Cancer Res. 2012, 72, 2791–2801. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  122. Poillet-Perez, L.; Sharp, D.W.; Yang, Y.; Laddha, S.V.; Ibrahim, M.; Bommareddy, P.K.; Hu, Z.S.; Vieth, J.; Haas, M.; Bosenberg, M.W.; et al. Autophagy Promotes Growth of Tumors with High Mutational Burden by Inhibiting a T-Cell Immune Response. Nat. Cancer 2020, 1, 923–934. [Google Scholar] [CrossRef] [PubMed]
  123. Wang, H.; Yao, H.; Li, C.; Shi, H.; Lan, J.; Li, Z.; Zhang, Y.; Liang, L.; Fang, J.-Y.; Xu, J. HIP1R Targets PD-L1 to Lysosomal Degradation to Alter T Cell–Mediated Cytotoxicity. Nat. Chem. Biol. 2019, 15, 42–50. [Google Scholar] [CrossRef]
  124. Yao, H.; Lan, J.; Li, C.; Shi, H.; Brosseau, J.-P.; Wang, H.; Lu, H.; Fang, C.; Zhang, Y.; Liang, L.; et al. Inhibiting PD-L1 Palmitoylation Enhances T-Cell Immune Responses against Tumours. Nat. Biomed. Eng. 2019, 3, 306–317. [Google Scholar] [CrossRef]
  125. Chen, D.; Xie, J.; Fiskesund, R.; Dong, W.; Liang, X.; Lv, J.; Jin, X.; Liu, J.; Mo, S.; Zhang, T.; et al. Chloroquine Modulates Antitumor Immune Response by Resetting Tumor-Associated Macrophages toward M1 Phenotype. Nat. Commun. 2018, 9, 873. [Google Scholar] [CrossRef] [Green Version]
  126. Mgrditchian, T.; Arakelian, T.; Paggetti, J.; Noman, M.Z.; Viry, E.; Moussay, E.; Van Moer, K.; Kreis, S.; Guerin, C.; Buart, S.; et al. Targeting Autophagy Inhibits Melanoma Growth by Enhancing NK Cells Infiltration in a CCL5-Dependent Manner. Proc. Natl. Acad. Sci. USA 2017, 114, E9271–E9279. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  127. Ou, P.; Wen, L.; Liu, X.; Huang, J.; Huang, X.; Su, C.; Wang, L.; Ni, H.; Reizis, B.; Yang, C.Y. Thioesterase PPT1 Balances Viral Resistance and Efficient T Cell Crosspriming in Dendritic Cells. J. Exp. Med. 2019, 216, 2091–2112. [Google Scholar] [CrossRef]
  128. Ren, Y.; Cao, L.; Wang, L.; Zheng, S.; Zhang, Q.; Guo, X.; Li, X.; Chen, M.; Wu, X.; Furlong, F.; et al. Autophagic Secretion of HMGB1 from Cancer-Associated Fibroblasts Promotes Metastatic Potential of Non-Small Cell Lung Cancer Cells via NFκB Signaling. Cell Death Dis. 2021, 12, 858. [Google Scholar] [CrossRef]
  129. Remon, J.; Besse, B.; Soria, J.-C. Successes and Failures: What Did We Learn from Recent First-Line Treatment Immunotherapy Trials in Non-Small Cell Lung Cancer? BMC Med. 2017, 15, 55. [Google Scholar] [CrossRef] [Green Version]
  130. Chen, C.; Zhang, F.; Zhou, N.; Gu, Y.-M.; Zhang, Y.-T.; He, Y.-D.; Wang, L.; Yang, L.-X.; Zhao, Y.; Li, Y.-M. Efficacy and Safety of Immune Checkpoint Inhibitors in Advanced Gastric or Gastroesophageal Junction Cancer: A Systematic Review and Meta-Analysis. Oncoimmunology 2019, 8, e1581547. [Google Scholar] [CrossRef] [Green Version]
  131. Kono, K.; Nakajima, S.; Mimura, K. Current Status of Immune Checkpoint Inhibitors for Gastric Cancer. Gastric Cancer 2020, 23, 565–578. [Google Scholar] [CrossRef] [PubMed]
  132. Ratner, L.; Waldmann, T.A.; Janakiram, M.; Brammer, J.E. Rapid Progression of Adult T-Cell Leukemia–Lymphoma after PD-1 Inhibitor Therapy. N. Engl. J. Med. 2018, 378, 1947–1948. [Google Scholar] [CrossRef]
  133. Swoboda, A.; Nanda, R. Immune Checkpoint Blockade for Breast Cancer. Cancer Treat. Res. 2018, 173, 155–165. [Google Scholar] [CrossRef]
  134. Pitt, J.M.; Vétizou, M.; Daillère, R.; Roberti, M.P.; Yamazaki, T.; Routy, B.; Lepage, P.; Boneca, I.G.; Chamaillard, M.; Kroemer, G.; et al. Resistance Mechanisms to Immune-Checkpoint Blockade in Cancer: Tumor-Intrinsic and -Extrinsic Factors. Immunity 2016, 44, 1255–1269. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  135. Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma | NEJM. Available online: https://www.nejm.org/doi/10.1056/NEJMoa1504030 (accessed on 18 May 2023).
  136. Deng, J.; Thennavan, A.; Dolgalev, I.; Chen, T.; Li, J.; Marzio, A.; Poirier, J.T.; Peng, D.H.; Bulatovic, M.; Mukhopadhyay, S.; et al. ULK1 Inhibition Overcomes Compromised Antigen Presentation and Restores Antitumor Immunity in LKB1-Mutant Lung Cancer. Nat. Cancer 2021, 2, 503–514. [Google Scholar] [CrossRef]
  137. Bestion, E.; Rachid, M.; Tijeras-Raballand, A.; Roth, G.; Decaens, T.; Ansaldi, C.; Mezouar, S.; Raymond, E.; Halfon, P. Targeting PPT1 with Ezurpimtrostat Sensitives Liver Tumor to Immunotherapy by Switching Cold into Hot Microenvironments. bioRxiv 2023, arXiv:2023.01.18.524541. [Google Scholar] [CrossRef]
  138. Infante, J.R.; Somer, B.G.; Park, J.O.; Li, C.-P.; Scheulen, M.E.; Kasubhai, S.M.; Oh, D.-Y.; Liu, Y.; Redhu, S.; Steplewski, K.; et al. A Randomised, Double-Blind, Placebo-Controlled Trial of Trametinib, an Oral MEK Inhibitor, in Combination with Gemcitabine for Patients with Untreated Metastatic Adenocarcinoma of the Pancreas. Eur. J. Cancer 2014, 50, 2072–2081. [Google Scholar] [CrossRef] [PubMed]
  139. Moretti, F.; Bergman, P.; Dodgson, S.; Marcellin, D.; Claerr, I.; Goodwin, J.M.; DeJesus, R.; Kang, Z.; Antczak, C.; Begue, D.; et al. TMEM41B Is a Novel Regulator of Autophagy and Lipid Mobilization. EMBO Rep. 2018, 19, e45889. [Google Scholar] [CrossRef]
  140. Morita, K.; Hama, Y.; Izume, T.; Tamura, N.; Ueno, T.; Yamashita, Y.; Sakamaki, Y.; Mimura, K.; Morishita, H.; Shihoya, W.; et al. Genome-Wide CRISPR Screen Identifies TMEM41B as a Gene Required for Autophagosome Formation. J. Cell. Biol. 2018, 217, 3817–3828. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  141. van Vliet, A.R.; Chiduza, G.N.; Maslen, S.L.; Pye, V.E.; Joshi, D.; De Tito, S.; Jefferies, H.B.J.; Christodoulou, E.; Roustan, C.; Punch, E.; et al. ATG9A and ATG2A Form a Heteromeric Complex Essential for Autophagosome Formation. Mol. Cell 2022, 82, 4324–4339.e8. [Google Scholar] [CrossRef] [PubMed]
  142. Chou, H.-Y.; Lee, Y.-T.; Lin, Y.J.; Wen, J.-K.; Peng, W.-H.; Hsieh, P.-L.; Lin, S.-Y.; Hung, C.-C.; Chen, G.-C. PTPN9-Mediated Dephosphorylation of VTI1B Promotes ATG16L1 Precursor Fusion and Autophagosome Formation. Autophagy 2021, 17, 2750–2765. [Google Scholar] [CrossRef] [PubMed]
  143. Kumar, S.; Gu, Y.; Abudu, Y.P.; Bruun, J.-A.; Jain, A.; Farzam, F.; Mudd, M.; Anonsen, J.H.; Rusten, T.E.; Kasof, G.; et al. Phosphorylation of Syntaxin 17 by TBK1 Controls Autophagy Initiation. Dev. Cell 2019, 49, 130–144.e6. [Google Scholar] [CrossRef] [Green Version]
  144. González-Rodríguez, P.; Delorme-Axford, E.; Bernard, A.; Keane, L.; Stratoulias, V.; Grabert, K.; Engskog-Vlachos, P.; Füllgrabe, J.; Klionsky, D.J.; Joseph, B. SETD2 Transcriptional Control of ATG14L/S Isoforms Regulates Autophagosome–Lysosome Fusion. Cell Death Dis. 2022, 13, 953. [Google Scholar] [CrossRef]
  145. Kocak, M.; Ezazi Erdi, S.; Jorba, G.; Maestro, I.; Farrés, J.; Kirkin, V.; Martinez, A.; Pless, O. Targeting Autophagy in Disease: Established and New Strategies. Autophagy 2022, 18, 473–495. [Google Scholar] [CrossRef]
  146. Békés, M.; Langley, D.R.; Crews, C.M. PROTAC Targeted Protein Degraders: The Past Is Prologue. Nat. Rev. Drug. Discov. 2022, 21, 181–200. [Google Scholar] [CrossRef]
  147. Kelm, J.M.; Pandey, D.S.; Malin, E.; Kansou, H.; Arora, S.; Kumar, R.; Gavande, N.S. PROTAC’ing Oncoproteins: Targeted Protein Degradation for Cancer Therapy. Mol. Cancer 2023, 22, 62. [Google Scholar] [CrossRef] [PubMed]
  148. Shifrut, E.; Carnevale, J.; Tobin, V.; Roth, T.L.; Woo, J.M.; Bui, C.; Li, P.J.; Diolaiti, M.; Ashworth, A.; Marson, A. Genome-Wide CRISPR Screens in Primary Human T Cells Reveal Key Regulators of Immune Function. Cell 2018, 175, 1958–1971.e15. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  149. Wang, Y.; Deng, S.; Xu, J. Proteasomal and Lysosomal Degradation for Specific and Durable Suppression of Immunotherapeutic Targets. Cancer Biol. Med. 2020, 17, 583–598. [Google Scholar] [CrossRef] [PubMed]
Cells 12 01702 g001 550
Figure 1. The molecular machinery of mammalian canonical autophagy and its pre-clinical and clinical targets. The complex autophagy process can be dissected into seven steps. (1) The induction phase of autophagy is controlled by the Unc-51-like autophagy activating kinase 1 complex (ULK1 complex), composed of ULK1/2 proteins and three other protein partners: the FAK family-interacting protein of 200 kD (FIP200), autophagy-related protein 13 (ATG13), and autophagy-related protein 101 (ATG101), to mediate the mammalian/mechanistic target of rapamycin (mTOR) signals. The ULK1 complex assimilates the stress signal received from mTOR complex 1 (mTORC1), activates it, and is responsible for the initiation of phagophore formation, the unclosed autophagosome structure. Immediately downstream of ULK1 complex activation, the class-III phosphatidylinositol 3-kinase (PI3K-III)/vacuolar protein sorting 34 (VPS34) complex, formed by VPS34 and by regulatory proteins vacuolar sorting protein 15 (VPS15), Beclin1 (BECN1), autophagy and beclin 1 regulator 1 (AMBRA1) and ATG14L, is phosphorylated and activated. This new complex participates in phagophore (2) nucleation and membrane isolation, elongation, and completion. It furthermore controls the conversion of phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PI3P). Local PI3P production occurs at a characteristic ER structure called the omegasome. PI3P then recruits the PI3P effector proteins WD repeat domain phosphoinositide-interacting proteins (WIPI) to the omegasome via interaction with their PI3P-binding domains. (3) Follows the preparation of phagophore membranes for phagophore recruitment to conjugation systems responsible for autophagosome formation. The two ubiquitin-like conjugation systems include the Atg12 conjugation system and the microtubule-associated protein 1A/1B-light chain 3 (LC3) conjugation system, both catalyzed by ATG7. The Atg12 conjugation system forms after ATG12 conjugates to ATG5, both stabilized by the ATG16L protein. The recruitment of the ATG12-ATG5–ATG16L1 complex starts provoking ATG3-mediated conjugation, crucial for the two conjugation systems’ end of execution. In the meantime, the LC3 conjugation machinery has conjugated microtubule-associated protein light chain 3 (LC3) with ATG4 forming LC3-I which is then converted into LC3-II after LC3-I conjugation with membrane-resident phosphatidylethanolamine (PE). The attached-LC3-II to the autophagosome serves as a docking site for the ubiquitin-binding protein (p62) and neighbor of the BRCA1 gene 1 protein (NBR1) that will trap organelles and proteins tagged by ubiquitination for their autophagic degradation. (4) Full execution of the conjugation systems and the presence of associated-LC3-II with PE on the forming autophagosome will participate in its elongation, arching, and closing. Sealing of the phagophore membranes gives rise to a double-layered vesicle called the autophagosome. (5) The autophagosome vesicle then matures before its (6) fusion with the lysosome, forming an autolysosome degradative structure. (7) Acidic lysosomal hydrolases are released nearby the previous embedded cellular components leading to their breakdown into essential products before being discharged and used for the biosynthesis of new components and to fuel cells. Multiple early (ULK and VPS34 inhibitors) and late (V-ATPase and PPT1 inhibitors) pharmacological autophagy blockers are currently under pre-clinical, and for some, clinical evaluation.
Figure 1. The molecular machinery of mammalian canonical autophagy and its pre-clinical and clinical targets. The complex autophagy process can be dissected into seven steps. (1) The induction phase of autophagy is controlled by the Unc-51-like autophagy activating kinase 1 complex (ULK1 complex), composed of ULK1/2 proteins and three other protein partners: the FAK family-interacting protein of 200 kD (FIP200), autophagy-related protein 13 (ATG13), and autophagy-related protein 101 (ATG101), to mediate the mammalian/mechanistic target of rapamycin (mTOR) signals. The ULK1 complex assimilates the stress signal received from mTOR complex 1 (mTORC1), activates it, and is responsible for the initiation of phagophore formation, the unclosed autophagosome structure. Immediately downstream of ULK1 complex activation, the class-III phosphatidylinositol 3-kinase (PI3K-III)/vacuolar protein sorting 34 (VPS34) complex, formed by VPS34 and by regulatory proteins vacuolar sorting protein 15 (VPS15), Beclin1 (BECN1), autophagy and beclin 1 regulator 1 (AMBRA1) and ATG14L, is phosphorylated and activated. This new complex participates in phagophore (2) nucleation and membrane isolation, elongation, and completion. It furthermore controls the conversion of phosphatidylinositol (PI) into phosphatidylinositol 3-phosphate (PI3P). Local PI3P production occurs at a characteristic ER structure called the omegasome. PI3P then recruits the PI3P effector proteins WD repeat domain phosphoinositide-interacting proteins (WIPI) to the omegasome via interaction with their PI3P-binding domains. (3) Follows the preparation of phagophore membranes for phagophore recruitment to conjugation systems responsible for autophagosome formation. The two ubiquitin-like conjugation systems include the Atg12 conjugation system and the microtubule-associated protein 1A/1B-light chain 3 (LC3) conjugation system, both catalyzed by ATG7. The Atg12 conjugation system forms after ATG12 conjugates to ATG5, both stabilized by the ATG16L protein. The recruitment of the ATG12-ATG5–ATG16L1 complex starts provoking ATG3-mediated conjugation, crucial for the two conjugation systems’ end of execution. In the meantime, the LC3 conjugation machinery has conjugated microtubule-associated protein light chain 3 (LC3) with ATG4 forming LC3-I which is then converted into LC3-II after LC3-I conjugation with membrane-resident phosphatidylethanolamine (PE). The attached-LC3-II to the autophagosome serves as a docking site for the ubiquitin-binding protein (p62) and neighbor of the BRCA1 gene 1 protein (NBR1) that will trap organelles and proteins tagged by ubiquitination for their autophagic degradation. (4) Full execution of the conjugation systems and the presence of associated-LC3-II with PE on the forming autophagosome will participate in its elongation, arching, and closing. Sealing of the phagophore membranes gives rise to a double-layered vesicle called the autophagosome. (5) The autophagosome vesicle then matures before its (6) fusion with the lysosome, forming an autolysosome degradative structure. (7) Acidic lysosomal hydrolases are released nearby the previous embedded cellular components leading to their breakdown into essential products before being discharged and used for the biosynthesis of new components and to fuel cells. Multiple early (ULK and VPS34 inhibitors) and late (V-ATPase and PPT1 inhibitors) pharmacological autophagy blockers are currently under pre-clinical, and for some, clinical evaluation.
Cells 12 01702 g001
Cells 12 01702 g002 550
Figure 2. Autophagy—a double-edged-word in cancer. Tumorigenesis starts with an oncogene mutation in the healthy tissue that makes cells grow and divide in an uncontrolled fashion, rapidly evolving from the hyperplasia-to-dysplasia stage followed by the in situ cancer stage. The altered cells exhibit changed morphology and behavior while they display an immature phenotype. Tumor cells then invade close-by areas until lymphatic and blood circulating system spread from the primary tumor site to distant sites, forming metastasis. Autophagy’s highly dynamic mechanism is permanently modulated during the tumorigenic process, working for both cancer suppression and promotion.
Figure 2. Autophagy—a double-edged-word in cancer. Tumorigenesis starts with an oncogene mutation in the healthy tissue that makes cells grow and divide in an uncontrolled fashion, rapidly evolving from the hyperplasia-to-dysplasia stage followed by the in situ cancer stage. The altered cells exhibit changed morphology and behavior while they display an immature phenotype. Tumor cells then invade close-by areas until lymphatic and blood circulating system spread from the primary tumor site to distant sites, forming metastasis. Autophagy’s highly dynamic mechanism is permanently modulated during the tumorigenic process, working for both cancer suppression and promotion.
Cells 12 01702 g002
Cells 12 01702 g003 550
Figure 3. (A) The main cellular components of the tumor microenvironment (TME) and (B) immune cells’ cross-talk with cancer cells associated with therapeutic strategies. (A) The TME encompasses immune cells, stromal cells, the extracellular matrix (ECM), and blood vessels. It is composed of cancer and heterogeneous non-malignant cells integrated into a complex molecules and matrix network. The relevant cellular components are T cells including cytotoxic T cells (CD8+), tumor-associated macrophages (TAMs), natural killer (NK) cells, cancer-associated fibroblasts (CAFs), dendritic cells (DCs), neutrophils, and monocytes. (B) MHC-I degradation through the autophagy process using the NBR1 cargo protein prevents TCR recognition leading to T cells’ anti-tumoral cytotoxic activity blockade. PPT1 inhibitor use allows for increased MHC-I molecule presentation on cancer cells’ surface, restoring T cells’ killing capacity towards malignant cells. PPT1 inhibitor treatment further leads to TAMs repolarization from the M2 to M1 phenotype, provoking pro-inflammatory secretion that boost NK cells’ and DCs’ infiltration into the tumor site, enabling T cells’ cytotoxic activity and infiltration. M1 abundance achieves cancer cell phagocytosis and killing, while the M2 phenotype’s low presence refrains not only cancer cells’ survival, invasion, and metastasis but increases T cells recruitment as well. PPT1 inhibitor use enhances immune checkpoint blockers’ efficacy, further dampening immune evasion.
Figure 3. (A) The main cellular components of the tumor microenvironment (TME) and (B) immune cells’ cross-talk with cancer cells associated with therapeutic strategies. (A) The TME encompasses immune cells, stromal cells, the extracellular matrix (ECM), and blood vessels. It is composed of cancer and heterogeneous non-malignant cells integrated into a complex molecules and matrix network. The relevant cellular components are T cells including cytotoxic T cells (CD8+), tumor-associated macrophages (TAMs), natural killer (NK) cells, cancer-associated fibroblasts (CAFs), dendritic cells (DCs), neutrophils, and monocytes. (B) MHC-I degradation through the autophagy process using the NBR1 cargo protein prevents TCR recognition leading to T cells’ anti-tumoral cytotoxic activity blockade. PPT1 inhibitor use allows for increased MHC-I molecule presentation on cancer cells’ surface, restoring T cells’ killing capacity towards malignant cells. PPT1 inhibitor treatment further leads to TAMs repolarization from the M2 to M1 phenotype, provoking pro-inflammatory secretion that boost NK cells’ and DCs’ infiltration into the tumor site, enabling T cells’ cytotoxic activity and infiltration. M1 abundance achieves cancer cell phagocytosis and killing, while the M2 phenotype’s low presence refrains not only cancer cells’ survival, invasion, and metastasis but increases T cells recruitment as well. PPT1 inhibitor use enhances immune checkpoint blockers’ efficacy, further dampening immune evasion.
Cells 12 01702 g003
Table
Table 1. Latest developed and tested autophagy inhibitors in cancer indication. AMPK: AMP-activated protein kinase, CQ: chloroquine, HCQ: hydroxychloroquine, N/A: not applicable, not available, NCT: national clinical trial, PPT1: palmitoyl-protein thioesterase 1, TBK1: TANK-binding kinase 1, ULK1/2: unc-51-like kinase 1/2, and V-ATPase: vacuolar ATPase.
Table 1. Latest developed and tested autophagy inhibitors in cancer indication. AMPK: AMP-activated protein kinase, CQ: chloroquine, HCQ: hydroxychloroquine, N/A: not applicable, not available, NCT: national clinical trial, PPT1: palmitoyl-protein thioesterase 1, TBK1: TANK-binding kinase 1, ULK1/2: unc-51-like kinase 1/2, and V-ATPase: vacuolar ATPase.
Autophagy StageCompoundMolecular TargetClinical Trial
InitiationMRT67307/MRT68921TBK1N/A
SBI-0206965ULK1-mediated phosphorylation, AMPKN/A
ULK-100/ULK-101ULK complexN/A
DCC-3116Phase 1/2 (NCT04892017)
NucleationSB02024VPS34N/A
SAR405N/A
Autophagosome–lysosome fusion249CV-ATPase subunit ATP6V1HData
Didemnin BPPT1N/A
CQ/HCQPhase 4
Lys05N/A
DQ661N/A
GNS561Phase 2 (NCT05448677)
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Share and Cite

MDPI and ACS Style

Bestion, E.; Raymond, E.; Mezouar, S.; Halfon, P. Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors. Cells 2023, 12, 1702. https://doi.org/10.3390/cells12131702

AMA Style

Bestion E, Raymond E, Mezouar S, Halfon P. Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors. Cells. 2023; 12(13):1702. https://doi.org/10.3390/cells12131702

Chicago/Turabian Style

Bestion, Eloïne, Eric Raymond, Soraya Mezouar, and Philippe Halfon. 2023. "Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors" Cells 12, no. 13: 1702. https://doi.org/10.3390/cells12131702

APA Style

Bestion, E., Raymond, E., Mezouar, S., & Halfon, P. (2023). Update on Autophagy Inhibitors in Cancer: Opening up to a Therapeutic Combination with Immune Checkpoint Inhibitors. Cells, 12(13), 1702. https://doi.org/10.3390/cells12131702

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop