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Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition

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A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: 30 June 2024 | Viewed by 6478

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Special Issue Editors

Dr. Patrick Ming-Kuen Tang

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Guest Editor

Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, The Chinese University of Hong Kong, Hong Kong 999077, Hong Kong
Interests: tumor microenvironment; drug resistance; immunotherapy; cell engineering; gene therapy
Special Issues, Collections and Topics in MDPI journals

Prof. Dr. Dongmei Zhang

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Guest Editor

College of Pharmacy, Jinan University, Guangzhou 510632, China
Interests: pharmacology; oncology; drug delivery; pericytes; angiogenesis; endothelial progenitor cell; extracellular vesicle; tyrosine kinase inhibitor
Special Issues, Collections and Topics in MDPI journals

Dr. Yan-Fang Xian

E-Mail Website
Guest Editor

School of Chinese Medicine, The Chinese University of Hong Kong, Hong Kong
Interests: Chinese medicine; pancreatic cancer; prostate cancer; herb-drug interaction; resistance
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

We are launching a Special Issue entitled “Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition” with the aim of rapidly sharing novel findings about anti-cancer therapy and their barriers in the research of molecular aspects of all types of human cancers.

We encourage submissions of high-quality manuscripts that provide novel mechanistic insights and details of the molecular signatures of oncogenic transformation, ranging from basic sciences to preclinical research as well as clinical study. Particularly, studies that focus on translating basic molecular knowledge to new applications in oncology are the most welcome.

The scope of this Special Issue includes, but is not limited to, the following topics:

Biological processes or molecular pathways for cancer development and progression.
Mechanisms of primary and secondary drug resistance.
Immunodynamics in tumour microenvironment regulating drug response.
Genomic profiling or any other ‘systems biology’ approaches in understanding acquired resistance.
Research that leads to novel therapies against advanced cancers and resistance.
Natural compound-based targeted therapy.

More published papers can be found in the closed Special Issue of our first edition: Advance in Targeted Cancer Therapy and Mechanisms of Resistance. We are looking forward to receiving your high-quality submissions.

Dr. Patrick Ming-Kuen Tang
Prof. Dr. Dongmei Zhang
Dr. Yan-Fang Xian
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

targeted therapy
drug resistance
tumor microenvironment
cancer progression
molecular profiling
immunosurveillance
immunotherapy
gene therapy
biomarker

Published Papers (5 papers)

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Research

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17 pages, 3277 KiB

Open AccessArticle

A Multi-Omics Approach Reveals Enrichment in Metabolites Involved in the Regulation of the Glutathione Pathway in LIN28B-Dependent Cancer Cells

by Matteo Stocchero, Diana Corallo, Silvia Bresolin, Marcella Pantile, Paola Pirillo, Roberta Bortolozzi, Sara Menegazzo, Daniele Boso, Giampietro Viola, Eugenio Baraldi, Alessandra Biffi, Giuseppe Giordano and Sanja Aveic

Int. J. Mol. Sci. 2024, 25(3), 1602; https://doi.org/10.3390/ijms25031602 - 27 Jan 2024

Viewed by 877

Abstract

The RNA-binding protein LIN28B, identified as an independent risk factor in high-risk neuroblastoma patients, is implicated in adverse treatment outcomes linked to metastasis and chemoresistance. Despite its clinical significance, the impact of LIN28B on neuroblastoma cell metabolism remains unexplored. This study employs a multi-omics approach, integrating transcriptome and metabolome data, to elucidate the global metabolic program associated with varying LIN28B expression levels over time. Our findings reveal that escalating LIN28B expression induces a significant metabolic rewiring in neuroblastoma cells. Specifically, LIN28B prompts a time-dependent increase in the release rate of metabolites related to the glutathione and aminoacyl-tRNA biosynthetic pathways, concomitant with a reduction in glucose uptake. These results underscore the pivotal role of LIN28B in governing neuroblastoma cell metabolism and suggest a potential disruption in the redox balance of LIN28B-bearing cells. This study offers valuable insights into the molecular mechanisms underlying LIN28B-associated adverse outcomes in neuroblastoma, paving the way for targeted therapeutic interventions. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)

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17 pages, 8516 KiB

Open AccessArticle

CRISPR/Cas9-Mediated CtBP1 Gene Editing Enhances Chemosensitivity and Inhibits Metastatic Potential in Esophageal Squamous Cell Carcinoma Cells

by Javed Akhtar, Muhammad Imran and Guanyu Wang

Int. J. Mol. Sci. 2023, 24(18), 14030; https://doi.org/10.3390/ijms241814030 - 13 Sep 2023

Viewed by 1211

Abstract

Innovative therapeutic strategies for esophageal squamous cell carcinoma (ESCC) are urgently required due to the limited effectiveness of standard chemotherapies. C-Terminal Binding Protein 1 (CtBP1) has been implicated in various cancers, including ESCC. However, the precise expression patterns and functional roles of CtBP1 in ESCC remain inadequately characterized. In this study, we aimed to investigate CtBP1 expression and its role in the resistance of ESCC to paclitaxel, an effective chemotherapeutic agent. Western blotting and immunofluorescence were applied to assess CtBP1 expression in the TE-1 and KYSE-50 cell lines. We observed the marked expression of CtBP1, which was associated with enhanced proliferation, invasion, and metastasis in these cell lines. Further, we successfully generated paclitaxel resistant ESCC cell lines and conducted cell viability assays. We employed the CRISPR/Cas9 genome editing system to disable the CtBP1 gene in ESCC cell lines. Through the analysis of the drug dose–response curve, we assessed the sensitivity of these cell lines in different treatment groups. Remarkably, CtBP1-disabled cell lines displayed not only improved sensitivity but also a remarkable inhibition of proliferation, invasion, and metastasis. This demonstrates that CtBP1 may promote ESCC cell malignancy and confer paclitaxel resistance. In summary, our study opens a promising avenue for targeted therapies, revealing the potential of CtBP1 inhibition to enhance the effectiveness of paclitaxel treatment for the personalized management of ESCC. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)

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13 pages, 2248 KiB

Open AccessArticle

AMPK/FOXO3a Pathway Increases Activity and/or Expression of ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 and Induces Radioresistance under Nutrient Starvation

by Yusuke Urushihara, Takuma Hashimoto, Yohei Fujishima and Yoshio Hosoi

Int. J. Mol. Sci. 2023, 24(16), 12828; https://doi.org/10.3390/ijms241612828 - 15 Aug 2023

Cited by 1 | Viewed by 1130

Abstract

Most solid tumors contain hypoxic and nutrient-deprived microenvironments. The cancer cells in these microenvironments have been reported to exhibit radioresistance. We have previously reported that nutrient starvation increases the expression and/or activity of ATM and DNA-PKcs, which are involved in the repair of DNA double-strand breaks induced by ionizing radiation. In the present study, to elucidate the molecular mechanisms underlying these phenomena, we investigated the roles of AMPK and FOXO3a, which play key roles in the cellular response to nutrient starvation. Nutrient starvation increased clonogenic cell survival after irradiation and increased the activity and/or expression of AMPKα, FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 in MDA-MB-231 cells. Knockdown of AMPKα using siRNA suppressed the activity and/or expression of FOXO3a, ATM, DNA-PKcs, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Knockdown of FOXO3a using siRNA suppressed the activity and/or expression of AMPKα, ATM, DNA-PKcs, FOXO3a, Src, EGFR, PDK1, and SOD2 under nutrient starvation. Nutrient starvation decreased the incidence of apoptosis after 8 Gy irradiation. Knockdown of FOXO3a increased the incidence of apoptosis after irradiation under nutrient starvation. AMPK and FOXO3a appear to be key molecules that induce radioresistance under nutrient starvation and may serve as targets for radiosensitization. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)

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Review

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16 pages, 924 KiB

Open AccessReview

Targeting BTK in B Cell Malignancies: From Mode of Action to Resistance Mechanisms

by Samir Mouhssine, Nawar Maher, Bassam Francis Matti, Alaa Fadhil Alwan and Gianluca Gaidano

Int. J. Mol. Sci. 2024, 25(6), 3234; https://doi.org/10.3390/ijms25063234 - 12 Mar 2024

Viewed by 1070

Abstract

The B cell receptor (BCR) signaling pathway plays a crucial role in B cell development and contributes to the pathogenesis of B cell neoplasms. In B cell malignancies, the BCR is constitutively active through both ligand-dependent and ligand-independent mechanisms, resulting in continuous Bruton tyrosine kinase (BTK) signaling activation, which provides a survival and proliferation advantage to the neoplastic clone. Among B cell malignancies, those in which the most significant results were obtained by treatment with BTK inhibitors (BTKi) include chronic lymphocytic leukemia, mantle cell lymphoma, lymphoplasmacytic lymphoma, and diffuse large B cell lymphoma. Covalent BTKi (namely ibrutinib, acalabrutinib, and zanubrutinib) functions by irreversibly blocking BTK through covalent binding to the cysteine residue 481 (Cys-481) in the ATP-binding domain. Despite the high efficacy and safety of BTKi treatment, a significant fraction of patients affected by B cell malignancies who are treated with these drugs experience disease relapse. Several mechanisms of resistance to covalent BTKi, including Cys-481 mutations of BTK, have been investigated in B cell malignancies. Non-covalent BTKi, such as pirtobrutinib, have been developed and proven effective in patients carrying both Cys-481-mutated and unmutated BTK. Moreover, targeting BTK with proteolysis-targeting chimeras (PROTACs) represents a promising strategy to overcome resistance to BTKi in B cell neoplasms. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)

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18 pages, 567 KiB

Open AccessReview

Genetic and Epigenetic Characteristics in Isolated Pancreatic Metastases of Clear-Cell Renal Cell Carcinoma

by Franz Sellner, Eva Compérat and Martin Klimpfinger

Int. J. Mol. Sci. 2023, 24(22), 16292; https://doi.org/10.3390/ijms242216292 - 14 Nov 2023

Viewed by 1308

Abstract

Isolated pancreatic metastases of renal cell carcinoma (IsPMRCC) are a rare manifestation of metastatic, clear-cell renal cell carcinoma (RCC) in which distant metastases occur exclusively in the pancreas. In addition to the main symptom of the isolated occurrence of pancreatic metastases, the entity surprises with additional clinical peculiarities: (a) the unusually long interval of about 9 years between the primary RCC and the onset of pancreatic metastases; (b) multiple pancreatic metastases occurring in 36% of cases; (c) favourable treatment outcomes with a 75% 5-year survival rate; and (d) volume and growth-rate dependent risk factors generally accepted to be relevant for overall survival in metastatic surgery are insignificant in isPMRCC. The genetic and epigenetic causes of exclusive pancreatic involvement have not yet been investigated and are currently unknown. Conversely, according to the few available data in the literature, the following genetic and epigenetic peculiarities can already be identified as the cause of the protracted course: 1. high genetic stability of the tumour cell clones in both the primary tumour and the pancreatic metastases; 2. a low frequency of copy number variants associated with aggressiveness, such as 9p, 14q and 4q loss; 3. in the chromatin-modifying genes, a decreased rate of PAB1 (3%) and an increased rate of PBRM1 (77%) defects are seen, a profile associated with a favourable course; 4. an increased incidence of KDM5C mutations, which, in common with increased PBRM1 alterations, is also associated with a favourable outcome; and 5. angiogenetic biomarkers are increased in tumour tissue, while inflammatory biomarkers are decreased, which explains the good response to TKI therapy and lack of sensitivity to IT. Full article

(This article belongs to the Special Issue Advance in Targeted Cancer Therapy and Mechanisms of Resistance—2nd Edition)

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