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Cancers
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The Renaissance of CDK Inhibition in Cancer Therapy
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The Renaissance of CDK Inhibition in Cancer Therapy

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (30 September 2021) | Viewed by 36420

Special Issue Editors

Dr. Francesca Pentimalli

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Guest Editor
Department of Medicine and Surgery, LUM University "Giuseppe DeGennaro", 70010 Casamassima, Italy
Interests: cell cycle; mesothelioma; DNA damage; tumor suppressor genes; RB family; p53; oncolytic viruses; cell death; CDK inhibitors; p27
Special Issues, Collections and Topics in MDPI journals
Prof. Dr. Antonio Giordano

E-Mail Website
Co-Guest Editor
1. Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA
2. Department of Medical Biotechnologies, University of Siena, Siena, Italy
Interests: cell cycle; tumor suppressor genes; RB family; CDK inhibitors; environment and cancer
Special Issues, Collections and Topics in MDPI journals
Dr. Paola Indovina

E-Mail Website
Co-Guest Editor
Sbarro Institute for Cancer Research and Molecular Medicine, Center for Biotechnology, College of Science and Technology, Temple University, Philadelphia, PA 19122, USA.
Interests: cell cycle; targeted therapy; RB family; tumor suppressors; SRC family kinases; WEE1 kinase; mesothelioma
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Progression through the cell cycle largely relies on protein phosphorylation events, which are mainly driven by the sequential activation of cyclin-dependent kinases (CDKs). Cell cycle deregulation, owing to aberrant CDK expression and other mechanisms affecting the cell cycle’s core machinery, is one of the main, well-established, features of cancer. Not surprisingly, the pharmacological inhibition of CDKs was devised early on as a strategy to halt tumorigenesis. The application of such a straightforward strategy, however, proved to be challenging and many hurdles have been encountered on the long road to the successful application of CDK inhibitors for cancer treatment. First, more than twenty CDKs have been identified in mammalian cells; all of these interact with different classes of cyclins and are involved in multiple functions beyond cell cycle regulation, including transcription, DNA replication, and DNA repair. Because of such complexity, the first generations of ‘pan-CDK’ inhibitors, which non-specifically targeted multiple kinases, failed in the clinical setting. The lack of a thorough understanding of the mechanism of action impaired the identification of biomarkers for patient selection and the design of possible effective combination strategies.

The recent development of selective CDK4/6 inhibitors has revolutionized the field, leading to the rapid approval by both the Food and Drug Administration and European Medical Agency of their clinical use for the treatment of advanced or metastatic . In just a few years, the number of new selective CDK inhibitors and their potential application in a variety of cancer types—as either single agents or in combination strategies—has increased impressively (with hundreds of currently ongoing trials registered on clinicaltrials.gov).

This Special Issue aims to present a collection of studies, both at the preclinical and clinical level, on the use of CDK inhibitors as an antitumoral strategy for different cancers, which will provide insights into the molecular mechanisms driving their action and possible resistance. This Special Issue also aims to learn how to make the most of this new powerful tool in the anticancer drug arsenal, how to combine it with other anticancer strategies, and how to identify those patients who can benefit from such new approaches for an immediate improvement. 

Dr. Francesca Pentimalli
Dr. Paola Indovina
Prof. Dr. Antonio Giordano
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 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. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). 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

  • cyclin dependent kinases (CDKs)
  • CDK inhibitors
  • cancer
  • cell cycle
  • cancer therapy
  • predictive biomarkers
  • acquired resistance
  • drug combination strategies

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Published Papers (7 papers)

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Research

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16 pages, 1954 KiB  
Article
CDK6 Degradation Is Counteracted by p16INK4A and p18INK4C in AML
by Belinda S. Schmalzbauer, Teresemary Thondanpallil, Gerwin Heller, Alessia Schirripa, Clio-Melina Sperl, Isabella M. Mayer, Vanessa M. Knab, Sofie Nebenfuehr, Markus Zojer, André C. Mueller, Frédéric Fontaine, Thorsten Klampfl, Veronika Sexl and Karoline Kollmann
Cancers 2022, 14(6), 1554; https://doi.org/10.3390/cancers14061554 - 18 Mar 2022
Cited by 7 | Viewed by 3435
Abstract
Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. [...] Read more.
Cyclin-dependent kinase 6 (CDK6) represents a novel therapeutic target for the treatment of certain subtypes of acute myeloid leukaemia (AML). CDK4/6 kinase inhibitors have been widely studied in many cancer types and their effects may be limited by primary and secondary resistance mechanisms. CDK4/6 degraders, which eliminate kinase-dependent and kinase-independent effects, have been suggested as an alternative therapeutic option. We show that the efficacy of the CDK6-specific protein degrader BSJ-03-123 varies among AML subtypes and depends on the low expression of the INK4 proteins p16INK4A and p18INK4C. INK4 protein levels are significantly elevated in KMT2A-MLLT3+ cells compared to RUNX1-RUNX1T1+ cells, contributing to the different CDK6 degradation efficacy. We demonstrate that CDK6 complexes containing p16INK4A or p18INK4C are protected from BSJ-mediated degradation and that INK4 levels define the proliferative response to CDK6 degradation. These findings define INK4 proteins as predictive markers for CDK6 degradation-targeted therapies in AML. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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Review

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20 pages, 2543 KiB  
Review
The Renaissance of CDK Inhibitors in Breast Cancer Therapy: An Update on Clinical Trials and Therapy Resistance
by Mary Abdelmalak, Rajanbir Singh, Mohammed Anwer, Pavel Ivanchenko, Amritdeep Randhawa, Myra Ahmed, Anthony W. Ashton, Yanming Du, Xuanmao Jiao and Richard Pestell
Cancers 2022, 14(21), 5388; https://doi.org/10.3390/cancers14215388 - 1 Nov 2022
Cited by 13 | Viewed by 5481
Abstract
Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are [...] Read more.
Cyclin-dependent kinases (CDKs) govern cell-cycle checkpoint transitions necessary for cancer cell proliferation. Recent developments have illustrated nuanced important differences between mono CDK inhibitor (CDKI) treatment and the combination therapies of breast cancers. The CDKIs that are currently FDA-approved for breast cancer therapy are oral agents that selectively inhibit CDK4 and CDK6, include palbociclib (Ibrance), ribociclib (Kisqali), and abemaciclib (Verzenio). CDKI therapy is effective in hormone receptor positive (HR+), and human epidermal growth factor receptor two negative (HER2−) advanced breast cancers (ABC) malignancies, but remains susceptible due to estrogen and progesterone receptor overexpression. Adding a CDK4/6I to endocrine therapy increases efficacy and delays disease progression. Given the side effects of CDKI, identifying potential new treatments to enhance CDKI effectiveness is essential. Recent long-term studies with Palbociclib, including the PALLAS and PENELOPE B, which failed to meet their primary endpoints of influencing progression-free survival, suggest a deeper mechanistic understanding of cyclin/CDK functions is required. The impact of CDKI on the anti-tumor immune response represents an area of great promise. CDKI therapy resistance that arises provides the opportunity for specific types of new therapies currently in clinical trials. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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25 pages, 1050 KiB  
Review
The Emerging Role of Cyclin-Dependent Kinase Inhibitors in Treating Diet-Induced Obesity: New Opportunities for Breast and Ovarian Cancers?
by Reyes Benot-Dominguez, Annamaria Cimini, Daniela Barone, Antonio Giordano and Francesca Pentimalli
Cancers 2022, 14(11), 2709; https://doi.org/10.3390/cancers14112709 - 30 May 2022
Cited by 3 | Viewed by 2640
Abstract
Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that [...] Read more.
Overweight and obesity constitute the most impactful lifestyle-dependent risk factors for cancer and have been tightly linked to a higher number of tumor-related deaths nowadays. The excessive accumulation of energy can lead to an imbalance in the level of essential cellular biomolecules that may result in inflammation and cell-cycle dysregulation. Nutritional strategies and phytochemicals are gaining interest in the management of obesity-related cancers, with several ongoing and completed clinical studies that support their effectiveness. At the same time, cyclin-dependent kinases (CDKs) are becoming an important target in breast and ovarian cancer treatment, with various FDA-approved CDK4/6 inhibitors that have recently received more attention for their potential role in diet-induced obesity (DIO). Here we provide an overview of the most recent studies involving nutraceuticals and other dietary strategies affecting cell-cycle pathways, which might impact the management of breast and ovarian cancers, as well as the repurposing of already commercialized chemotherapeutic options to treat DIO. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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39 pages, 7132 KiB  
Review
The Renaissance of Cyclin Dependent Kinase Inhibitors
by Tobias Ettl, Daniela Schulz and Richard Josef Bauer
Cancers 2022, 14(2), 293; https://doi.org/10.3390/cancers14020293 - 7 Jan 2022
Cited by 33 | Viewed by 9197
Abstract
Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor [...] Read more.
Cyclin-dependent kinases (CDK) regulate cell cycle progression. During tumor development, altered expression and availability of CDKs strongly contribute to impaired cell proliferation, a hallmark of cancer. In recent years, targeted inhibition of CDKs has shown considerable therapeutic benefit in a variety of tumor entities. Their success is reflected in clinical approvals of specific CDK4/6 inhibitors for breast cancer. This review provides a detailed insight into the molecular mechanisms of CDKs as well as a general overview of CDK inhibition. It also summarizes the latest research approaches and current advances in the treatment of head and neck cancer with CDK inhibitors. Instead of monotherapies, combination therapies with CDK inhibitors may especially provide promising results in tumor therapy. Indeed, recent studies have shown a synergistic effect of CDK inhibition together with chemo- and radio- and immunotherapy in cancer treatment to overcome tumor evasion, which may lead to a renaissance of CDK inhibitors. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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21 pages, 3869 KiB  
Review
Inhibitors, PROTACs and Molecular Glues as Diverse Therapeutic Modalities to Target Cyclin-Dependent Kinase
by Sandeep Rana, Jayapal Reddy Mallareddy, Sarbjit Singh, Lidia Boghean and Amarnath Natarajan
Cancers 2021, 13(21), 5506; https://doi.org/10.3390/cancers13215506 - 2 Nov 2021
Cited by 19 | Viewed by 7586
Abstract
The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this [...] Read more.
The cyclin-dependent kinase (CDK) family of proteins play prominent roles in transcription, mRNA processing, and cell cycle regulation, making them attractive cancer targets. Palbociclib was the first FDA-approved CDK inhibitor that non-selectively targets the ATP binding sites of CDK4 and CDK6. In this review, we will briefly inventory CDK inhibitors that are either part of over 30 active clinical trials or recruiting patients. The lack of selectivity among CDKs and dose-limiting toxicities are major challenges associated with the development of CDK inhibitors. Proteolysis Targeting Chimeras (PROTACs) and Molecular Glues have emerged as alternative therapeutic modalities to target proteins. PROTACs and Molecular glues utilize the cellular protein degradation machinery to destroy the target protein. PROTACs are heterobifunctional molecules that form a ternary complex with the target protein and E3-ligase by making two distinct small molecule–protein interactions. On the other hand, Molecular glues function by converting the target protein into a “neo-substrate” for an E3 ligase. Unlike small molecule inhibitors, preclinical studies with CDK targeted PROTACs have exhibited improved CDK selectivity. Moreover, the efficacy of PROTACs and molecular glues are not tied to the dose of these molecular entities but to the formation of the ternary complex. Here, we provide an overview of PROTACs and molecular glues that modulate CDK function as emerging therapeutic modalities. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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14 pages, 12320 KiB  
Review
Implications of TGFβ Signaling and CDK Inhibition for the Treatment of Breast Cancer
by Joseph T. Decker, Jeffrey A. Ma, Lonnie D. Shea and Jacqueline S. Jeruss
Cancers 2021, 13(21), 5343; https://doi.org/10.3390/cancers13215343 - 25 Oct 2021
Cited by 6 | Viewed by 2564
Abstract
TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant [...] Read more.
TGFβ signaling enacts tumor-suppressive functions in normal cells through promotion of several cell regulatory actions including cell-cycle control and apoptosis. Canonical TGFβ signaling proceeds through phosphorylation of the transcription factor, SMAD3, at the C-terminus of the protein. During oncogenic progression, this tumor suppressant phosphorylation of SMAD3 can be inhibited. Overexpression of cyclins D and E, and subsequent hyperactivation of cyclin-dependent kinases 2/4 (CDKs), are often observed in breast cancer, and have been associated with poor prognosis. The noncanonical phosphorylation of SMAD3 by CDKs 2 and 4 leads to the inhibition of tumor-suppressive function of SMAD3. As a result, CDK overactivation drives oncogenic progression, and can be targeted to improve clinical outcomes. This review focuses on breast cancer, and highlights advances in the understanding of CDK-mediated noncanonical SMAD3 phosphorylation. Specifically, the role of aberrant TGFβ signaling in oncogenic progression and treatment response will be examined to illustrate the potential for therapeutic discovery in the context of cyclins/CDKs and SMAD3. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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21 pages, 1993 KiB  
Systematic Review
Endocrine-Based Treatments in Clinically-Relevant Subgroups of Hormone Receptor-Positive/HER2-Negative Metastatic Breast Cancer: Systematic Review and Meta-Analysis
by Francesco Schettini, Mario Giuliano, Fabiola Giudici, Benedetta Conte, Pietro De Placido, Sergio Venturini, Carla Rognoni, Angelo Di Leo, Mariavittoria Locci, Guy Jerusalem, Lucia Del Mastro, Fabio Puglisi, PierFranco Conte, Michelino De Laurentiis, Lajos Pusztai, Mothaffar F. Rimawi, Rachel Schiff, Grazia Arpino, Sabino De Placido, Aleix Prat and Daniele Generaliadd Show full author list remove Hide full author list
Cancers 2021, 13(6), 1458; https://doi.org/10.3390/cancers13061458 - 22 Mar 2021
Cited by 18 | Viewed by 4169
Abstract
A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted [...] Read more.
A precise assessment of the efficacy of first-/second-line endocrine therapies (ET) ± target therapies (TT) in clinically-relevant subgroups of hormone receptor-positive (HR+)/HER2-negative metastatic breast cancer (MBC) has not yet been conducted. To improve our current knowledge and support clinical decision-making, we thus conducted a systematic literature search to identify all first-/second-line phase II/III randomized clinical trials (RCT) of currently approved or most promising ET ± TT. Then, we performed a meta-analysis to assess progression-free (PFS) and/or overall survival (OS) benefit in several clinically-relevant prespecified subgroups. Thirty-five RCT were included (17,595 patients). Pooled results show significant reductions in the risk of relapse or death of 26–41% and 12–27%, respectively, depending on the clinical subgroup. Combination strategies proved to be more effective than single-agent ET (PFS hazard ratio (HR) range for combinations: 0.60–0.65 vs. HR range for single agent ET: 0.59–1.37; OS HR range for combinations: 0.74–0.87 vs. HR range for single agent ET: 0.68–0.98), with CDK4/6-inhibitors(i) + ET being the most effective regimen. Single agent ET showed comparable efficacy with ET+TT combinations in non-visceral (p = 0.63) and endocrine sensitive disease (p = 0.79), while mTORi-based combinations proved to be a valid therapeutic option in endocrine-resistant tumors, as well as PI3Ki + ET in PIK3CA-mutant tumors. These results strengthen international treatment guidelines and can aid therapeutic decision-making. Full article
(This article belongs to the Special Issue The Renaissance of CDK Inhibition in Cancer Therapy)
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