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Biomedicines
Special Issues
Advanced Research of Targeting CDKs in Oncology
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Advanced Research of Targeting CDKs in Oncology

A special issue of Biomedicines (ISSN 2227-9059). This special issue belongs to the section "Molecular and Translational Medicine".

Deadline for manuscript submissions: closed (31 May 2023) | Viewed by 3907

Special Issue Editor

Dr. Sara Ravaioli

E-Mail Website
Guest Editor
Biosciences Laboratory, IRCCS Istituto Romagnolo per lo Studio dei Tumori (IRST) “Dino Amadori”, 47014 Meldola, Italy
Interests: breast cancer; translational research; oncology; biomarkers

Special Issue Information

Dear Colleagues,

Cyclin-dependent kinases (CDKs) are cell cycle key regulators overexpressed and deemed as therapeutic targets in many cancer types. CDK proteins lead to G1/S progression through phosphorylation of Rb facilitating tumorigenesis. The first clinically approved CDK4/6 inhibitors (palbociclib, ribociclib, and abemaciclib) have uncovered the great importance of targeting this pathway, demonstrating efficacy, but the identification of predictive biomarkers and the mechanisms underlying drug resistance still represent major unmet clinical needs. Moreover, new therapeutic approaches of combination therapy are emerging as a hot topic in this context to overcome resistance and should be explored. This Special Issue welcomes both basic studies and translational research including original articles, short communications, reviews, and commentaries, focused on anticancer strategies against CDKs. Special attention will be given to manuscripts reporting the molecular mechanisms of drug resistance, predictive biomarkers, and new therapeutic approaches in targeting CDK pathway in cancer.

Dr. Sara Ravaioli
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. Biomedicines is an international peer-reviewed open access monthly 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 2600 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

  • CDK4/6
  • target therapy
  • CDK inhibitor
  • cell cycle
  • drug resistance
  • biomarkers
  • anticancer therapy

 

Published Papers (2 papers)

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Research

11 pages, 798 KiB  
Article
An Italian Real-World Study Highlights the Importance of Some Clinicopathological Characteristics Useful in Identifying Metastatic Breast Cancer Patients Resistant to CDK4/6 Inhibitors and Hormone Therapy
by Roberta Maltoni, Andrea Roncadori, William Balzi, Massimiliano Mazza, Fabio Nicolini, Michela Palleschi, Paola Ulivi and Sara Bravaccini
Biomedicines 2024, 12(3), 498; https://doi.org/10.3390/biomedicines12030498 - 22 Feb 2024
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Abstract
Background: Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a large number of patients present disease progression due [...] Read more.
Background: Cyclin-dependent kinase 4 and 6 (CDK4 and CDK6) inhibitors have changed the therapeutic management of hormone receptor-positive (HR+) metastatic breast cancer (mBC) by targeting the cell cycle machinery and overcoming endocrine resistance. However, a large number of patients present disease progression due to cancer cells resisting CDK4/6 inhibitors. Our research considers which clinicopathological characteristics could be useful in identifying patients who might respond to CDK4/6 inhibitors by analyzing a retrospective case series of patients with HR+ mBC who were treated with hormone therapy plus CDK4/6 inhibitors. Methods: Approximately 177 mBC patients were enrolled, of whom 66 were treated with CD4/6 inhibitors plus letrozole and 111 were treated with CDK4/6 inhibitors and fulvestrant. A multistate model was used. Results: A low body surface area and older age were associated with an increased risk of developing neutropenia. A high Ki67 index, the presence of visceral metastases, and not having previously undergone adjuvant chemotherapy were prognostic factors of disease progression/death. As expected, some of the neutropenic patients who had previously undergone multiple lines of treatment were at a higher risk of disease progression/death. Furthermore, neutropenia status was associated with a more than doubled risk of progression/death compared to patients without neutropenia (HR = 2.311; p = 0.025). Conclusions: Having identified certain factors that could be associated with the development of neutropenia and considering that neutropenia itself is associated with an increased risk of progression, we believe that the baseline characteristics should be taken into account to reduce cases of neutropenia and disease progression. Full article
(This article belongs to the Special Issue Advanced Research of Targeting CDKs in Oncology)
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20 pages, 4450 KiB  
Article
Dbf4-Cdc7 (DDK) Inhibitor PHA-767491 Displays Potent Anti-Proliferative Effects via Crosstalk with the CDK2-RB-E2F Pathway
by Tekle Pauzaite, James Tollitt, Betul Sopaci, Louise Caprani, Olivia Iwanowytsch, Urvi Thacker, John G. Hardy, Sarah L. Allinson and Nikki A. Copeland
Biomedicines 2022, 10(8), 2012; https://doi.org/10.3390/biomedicines10082012 - 19 Aug 2022
Cited by 1 | Viewed by 2353
Abstract
Precise regulation of DNA replication complex assembly requires cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) activities to activate the replicative helicase complex and initiate DNA replication. Chemical probes have been essential in the molecular analysis of DDK-mediated regulation of MCM2-7 activation and the [...] Read more.
Precise regulation of DNA replication complex assembly requires cyclin-dependent kinase (CDK) and Dbf4-dependent kinase (DDK) activities to activate the replicative helicase complex and initiate DNA replication. Chemical probes have been essential in the molecular analysis of DDK-mediated regulation of MCM2-7 activation and the initiation phase of DNA replication. Here, the inhibitory activity of two distinct DDK inhibitor chemotypes, PHA-767491 and XL-413, were assessed in cell-free and cell-based proliferation assays. PHA-767491 and XL-413 show distinct effects at the level of cellular proliferation, initiation of DNA replication and replisome activity. XL-413 and PHA-767491 both reduce DDK-specific phosphorylation of MCM2 but show differential potency in prevention of S-phase entry. DNA combing and DNA replication assays show that PHA-767491 is a potent inhibitor of the initiation phase of DNA replication but XL413 has weak activity. Importantly, PHA-767491 decreased E2F-mediated transcription of the G1/S regulators cyclin A2, cyclin E1 and cyclin E2, and this effect was independent of CDK9 inhibition. Significantly, the enhanced inhibitory profile of PHA-767491 is mediated by potent inhibition of both DDK and the CDK2-Rb-E2F transcriptional network, that provides the molecular basis for its increased anti-proliferative effects in RB+ cancer cell lines. Full article
(This article belongs to the Special Issue Advanced Research of Targeting CDKs in Oncology)
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