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Senescence as a therapeutically relevant response to CDK4/6 inhibitors
Open accessAbstract
Cyclin-dependent kinases 4 and 6 (CDK4/6) phosphorylate and inhibit retinoblastoma (RB) family proteins. Hyperphosphorylated RB releases E2F transcription factors, activating a transcriptional program that initiates S phase. Due to the critical role that this pathway has in regulating cell cycle progression, inhibiting CDK4/6 is an attractive therapeutic strategy. Indeed, CDK4/6 inhibitors in combination with antiestrogens produce a significant benefit in patients with ER+/HER2- breast cancer. Clinical trials are currently investigating if the use of CDK4/6 inhibitors alone or in combination can be extended to other cancer types. Inhibition of CDK4/6 can result in different cell fates such as quiescence, senescence, or apoptosis. Senescence is a stress response that can be induced by stimuli that include oncogenic activation, chemotherapy, irradiation, and targeted therapies such as CDK4/6 inhibitors. Senescent cells undergo a stable cell cycle arrest and produce a bioactive secretome that remodels their microenvironment and engages the immune system. In this review, we analyze the therapeutic relevance of senescence induction by CDK4/6 inhibitors. We also discuss how different therapies, including checkpoint inhibitors and drugs targeting MEK or PI3K, can be used in combination with CDK4/6 inhibitors to reinforce or exploit senescence. Recently, a lot of effort has been put into identifying compounds that selectively kill senescent cells (termed senolytics). Thus, sequential treatment with senolytics might be an additional strategy to potentiate the antitumor effects of CDK4/6 inhibitors.
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“Some targeted therapies, such as inhibitors of aurora kinase or CDK4/6 also trigger tumor senescence and show promise in treating a number of cancers (Wagner and Gil 2020).”
From Senescence and the SASP: many therapeutic avenues (2020) · cites this paper as Wagner and Gil 2020
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Metadata
- Authors
- Wagner, V., & Gil, J.
- Affiliations
- MRC London Institute of Medical Sciences (GB)
- Corresponding author
- Gil, Jesús
- Venue
- Oncogene
- Published
- 2020-06-15
- Volume
- 39
- Issue
- 29
- Pages
- 5165-5176
- ISSN
- 0950-9232 (ISSN-L)
- 1476-5594
- PMC
- PMC7610384
- OpenAlex
- W3034793718
- Cited by
- 148
- References
- 107
- Citations by year
- 2026: 25 · 2025: 30 · 2024: 22 · 2023: 28 · 2022: 20 · 2021: 20 · 2020: 3
- FWCI
- 2.26
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Oncogene (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- Cancer Research UK (C15075/A28647)
- RCUK | Medical Research Council (MC_U120085810)
- German Cancer Aid Mildred- Scheel-Postdoc Program
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Health Sciences › Medicine › Oncology › Advanced Breast Cancer Therapies
- Health Sciences › Medicine › Oncology › Cancer-related Molecular Pathways
- Keywords
- cellular senescence, CDK4/6 inhibitors, retinoblastoma protein, E2F transcription factors, cell cycle arrest, senescence-associated secretome, senolytics, combination therapy, immune checkpoint inhibitors, MEK inhibitors, PI3K inhibitors, ER-positive HER2-negative breast cancer, antiestrogens, tumor microenvironment
- MeSH terms
- Female, Humans, Male, Cellular Senescence, Cyclin-Dependent Kinase 4, Cyclin-Dependent Kinase 6, Tumor Microenvironment
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