Senescence as a therapeutically relevant response to CDK4/6 inhibitors.

Content Provider	Europe PMC
Author	Wagner, Verena Gil, Jesús
Abstract	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 anti-estrogens 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.
ISSN	09509232
Volume Number	39
PubMed Central reference number	PMC7610384
Issue Number	29
PubMed reference number	32541838
Journal	Oncogene
e-ISSN	14765594
DOI	10.1038/s41388-020-1354-9
Language	English
Publisher Date	2020-06-15
Access Restriction	Open
Rights License	Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms
Subject Keyword	Senescence CDK4 CDK6 CDK4/6 inhibitors Palbociclib Abemaciclib Ribociclib
Content Type	Text
Resource Type	Article
Subject	Genetics Molecular Biology Cancer Research