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Senescence as a therapeutically relevant response to CDK4/6 inhibitors

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 pro...

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Detalles Bibliográficos
Autores principales: Wagner, Verena, Gil, Jesús
Formato: Online Artículo Texto
Lenguaje:English
Publicado: 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610384/
https://www.ncbi.nlm.nih.gov/pubmed/32541838
http://dx.doi.org/10.1038/s41388-020-1354-9
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author Wagner, Verena
Gil, Jesús
author_facet Wagner, Verena
Gil, Jesús
author_sort Wagner, Verena
collection PubMed
description 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.
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spelling pubmed-76103842021-03-22 Senescence as a therapeutically relevant response to CDK4/6 inhibitors Wagner, Verena Gil, Jesús Oncogene Article 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. 2020-07-01 2020-06-15 /pmc/articles/PMC7610384/ /pubmed/32541838 http://dx.doi.org/10.1038/s41388-020-1354-9 Text en http://www.nature.com/authors/editorial_policies/license.html#termsUsers 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
spellingShingle Article
Wagner, Verena
Gil, Jesús
Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title_full Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title_fullStr Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title_full_unstemmed Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title_short Senescence as a therapeutically relevant response to CDK4/6 inhibitors
title_sort senescence as a therapeutically relevant response to cdk4/6 inhibitors
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7610384/
https://www.ncbi.nlm.nih.gov/pubmed/32541838
http://dx.doi.org/10.1038/s41388-020-1354-9
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