Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
7.4
5.2
Journals
Cancers
Special Issues
Targeting Cyclin-Dependent Kinases in Human Cancers
share announcement

Targeting Cyclin-Dependent Kinases in Human Cancers

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

Deadline for manuscript submissions: closed (31 March 2021) | Viewed by 20432

Special Issue Editor

Dr. Claudia Maletzki

E-Mail Website
Guest Editor
Universitätsmedizin Rostock Zentrum für Innere Medizin, Universität Rostock, Rostock, Germany
Interests: tumor models; immunotherapy; personalized treatment; T cells; tumor microenvironment
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Cell cycle dysregulation is a hallmark of cancer. In normal cells, Cyclin-dependent kinases (CDKs) govern transition from G1 to S-phase finally enabling proliferation.
Quite reasonably, pharmacologic inhibition of CDKs has great therapeutic potential for both solid tumors and hematological malignancies. Ever since its discovery and therapeutic application, much of the focus has been on their direct antitumoral effects, contributing to the recent clinical approval of dual CDK4/6 inhibitors for treatment of patients with hormone receptor-positive, HER2-negative breast cancer as well as in small cell lung cancer patients to reduce chemotherapy-induced myelosuppression.
Emerging evidence reveals that a holistic view of both tumor cells and the tumor microenvironment is crucial for the rationale application of CDKi. In colorectal carcinomas for instance, CDKi treatment induces a T cell inflamed phenotype and enhances the susceptibility towards immune-checkpoint blocking antibodies. Comparable results gathered from murine tumor models support these findings and clinical trials are underway to prove the advantage of such combinations including their scheduling and/or sequencing.
Still, CDKi increase genomic instability in tumor cells and drug-resistant tumors can emerge under the selection pressure even after prolonged treatments. Besides, predictive biomarkers of response are scarce and currently limited to CCND1 and CDKN2A genomic alterations.

This special issue will provide a comprehensive overview and novel insights on antitumoral and immune-stimulating effects of CDKi, underlying mechanisms of response, strategies to combat drug resistance and the potential risk of developing secondary malignancies at later stages that improve our understanding for subsequent clinical application.

Dr. Claudia Maletzki
Guest Editor

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. 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

  • targeted therapy
  • radiation
  • resistance mechanisms
  • biomarkers
  • pharmacokinetics
  • senescence
  • clinical response rates
  • combination strategies

Published Papers (4 papers)

Download All Papers
Order results
Result details
Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:

Research

Jump to: Review

20 pages, 4678 KiB  
Article
The Individual Effects of Cyclin-Dependent Kinase Inhibitors on Head and Neck Cancer Cells—A Systematic Analysis
by Nina Schoenwaelder, Inken Salewski, Nadja Engel, Mareike Krause, Björn Schneider, Michael Müller, Christin Riess, Heiko Lemcke, Anna Skorska, Christina Grosse-Thie, Christian Junghanss and Claudia Maletzki
Cancers 2021, 13(10), 2396; https://doi.org/10.3390/cancers13102396 - 15 May 2021
Cited by 7 | Viewed by 2800
Abstract
Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, [...] Read more.
Cyclin-dependent kinase inhibitors (CDKi´s) display cytotoxic activity against different malignancies, including head and neck squamous cell carcinomas (HNSCC). By coordinating the DNA damage response, these substances may be combined with cytostatics to enhance cytotoxicity. Here, we investigated the influence of different CDKi´s (palbociclib, dinaciclib, THZ1) on two HNSCC cell lines in monotherapy and combination therapy with clinically-approved drugs (5-FU, Cisplatin, cetuximab). Apoptosis/necrosis, cell cycle, invasiveness, senescence, radiation-induced γ-H2AX DNA double-strand breaks, and effects on the actin filament were studied. Furthermore, the potential to increase tumor immunogenicity was assessed by analyzing Calreticulin translocation and immune relevant surface markers. Finally, an in vivo mouse model was used to analyze the effect of dinaciclib and Cisplatin combination therapy. Dinaciclib, palbociclib, and THZ1 displayed anti-neoplastic activity after low-dose treatment, while the two latter substances slightly enhanced radiosensitivity. Dinaciclib decelerated wound healing, decreased invasiveness, and induced MHC-I, accompanied by high amounts of surface-bound Calreticulin. Numbers of early and late apoptotic cells increased initially (24 h), while necrosis dominated afterward. Antitumoral effects of the selective CDKi palbociclib were weaker, but combinations with 5-FU potentiated effects of the monotherapy. Additionally, CDKi and CDKi/chemotherapy combinations induced MHC I, indicative of enhanced immunogenicity. The in vivo studies revealed a cell line-specific response with best tumor growth control in the combination approach. Global acting CDKi’s should be further investigated as targeting agents for HNSCC, either individually or in combination with selected drugs. The ability of dinaciclib to increase the immunogenicity of tumor cells renders this substance a particularly interesting candidate for immune-based oncological treatment regimens. Full article
(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)
►▼ Show Figures

Graphical abstract

Review

Jump to: Research

18 pages, 1286 KiB  
Review
Cyclin-Dependent Kinase Inhibitors in Hematological Malignancies—Current Understanding, (Pre-)Clinical Application and Promising Approaches
by Anna Richter, Nina Schoenwaelder, Sina Sender, Christian Junghanss and Claudia Maletzki
Cancers 2021, 13(10), 2497; https://doi.org/10.3390/cancers13102497 - 20 May 2021
Cited by 12 | Viewed by 3341
Abstract
Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing [...] Read more.
Genetically altered stem or progenitor cells feature gross chromosomal abnormalities, inducing modified ability of self-renewal and abnormal hematopoiesis. Cyclin-dependent kinases (CDK) regulate cell cycle progression, transcription, DNA repair and are aberrantly expressed in hematopoietic malignancies. Incorporation of CDK inhibitors (CDKIs) into the existing therapeutic regimens therefore constitutes a promising strategy. However, the complex molecular heterogeneity and different clinical presentation is challenging for selecting the right target and defining the ideal combination to mediate long-term disease control. Preclinical and early clinical data suggest that specific CDKIs have activity in selected patients, dependent on the existing rearrangements and mutations, potentially acting as biomarkers. Indeed, CDK6, expressed in hematopoietic cells, is a direct target of MLL fusion proteins often observed in acute leukemia and thus contributes to leukemogenesis. The high frequency of aberrancies in the retinoblastoma pathway additionally warrants application of CDKIs in hematopoietic neoplasms. In this review, we describe the preclinical and clinical advances recently made in the use of CDKIs. These include the FDA-approved CDK4/6 inhibitors, traditional and novel pan-CDKIs, as well as dual kinase inhibitors. We additionally provide an overview on molecular mechanisms of response vs. resistance and discuss open questions. Full article
(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)
►▼ Show Figures

Figure 1

31 pages, 7849 KiB  
Review
Targeting CDK9 for Anti-Cancer Therapeutics
by Ranadip Mandal, Sven Becker and Klaus Strebhardt
Cancers 2021, 13(9), 2181; https://doi.org/10.3390/cancers13092181 - 01 May 2021
Cited by 58 | Viewed by 7335
Abstract
Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to [...] Read more.
Cyclin Dependent Kinase 9 (CDK9) is one of the most important transcription regulatory members of the CDK family. In conjunction with its main cyclin partner—Cyclin T1, it forms the Positive Transcription Elongation Factor b (P-TEFb) whose primary function in eukaryotic cells is to mediate the positive transcription elongation of nascent mRNA strands, by phosphorylating the S2 residues of the YSPTSPS tandem repeats at the C-terminus domain (CTD) of RNA Polymerase II (RNAP II). To aid in this process, P-TEFb also simultaneously phosphorylates and inactivates a number of negative transcription regulators like 5,6-dichloro-1-β-D-ribofuranosylbenzimidazole (DRB) Sensitivity-Inducing Factor (DSIF) and Negative Elongation Factor (NELF). Significantly enhanced activity of CDK9 is observed in multiple cancer types, which is universally associated with significantly shortened Overall Survival (OS) of the patients. In these cancer types, CDK9 regulates a plethora of cellular functions including proliferation, survival, cell cycle regulation, DNA damage repair and metastasis. Due to the extremely critical role of CDK9 in cancer cells, inhibiting its functions has been the subject of intense research, resulting the development of multiple, increasingly specific small-molecule inhibitors, some of which are presently in clinical trials. The search for newer generation CDK9 inhibitors with higher specificity and lower potential toxicities and suitable combination therapies continues. In fact, the Phase I clinical trials of the latest, highly specific CDK9 inhibitor BAY1251152, against different solid tumors have shown good anti-tumor and on-target activities and pharmacokinetics, combined with manageable safety profile while the phase I and II clinical trials of another inhibitor AT-7519 have been undertaken or are undergoing. To enhance the effectiveness and target diversity and reduce potential drug-resistance, the future of CDK9 inhibition would likely involve combining CDK9 inhibitors with inhibitors like those against BRD4, SEC, MYC, MCL-1 and HSP90. Full article
(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)
►▼ Show Figures

Figure 1

27 pages, 2625 KiB  
Review
The Role of CDK5 in Tumours and Tumour Microenvironments
by Phuong Anh Do and Chang Hoon Lee
Cancers 2021, 13(1), 101; https://doi.org/10.3390/cancers13010101 - 31 Dec 2020
Cited by 23 | Viewed by 6094
Abstract
Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune [...] Read more.
Cyclin-dependent kinase 5 (CDK5), which belongs to the protein kinase family, regulates neuronal function but is also associated with cancer development and has been proposed as a target for cancer treatment. Indeed, CDK5 has roles in cell proliferation, apoptosis, angiogenesis, inflammation, and immune response. Aberrant CDK5 activation triggers tumour progression in numerous types of cancer. In this review, we summarise the role of CDK5 in cancer and neurons and CDK5 inhibitors. We expect that our review helps researchers to develop CDK5 inhibitors as treatments for refractory cancer. Full article
(This article belongs to the Special Issue Targeting Cyclin-Dependent Kinases in Human Cancers)
►▼ Show Figures

Figure 1

Show export options expand_more Show export options expand_less
Select all
Export citation of selected articles as:
 
Displaying articles 1-4
Back to TopTop