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Senescence as a therapeutically relevant response to CDK4/6 inhibitors

Oncogene volume 39, pages 5165–5176 (2020)Cite this article

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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 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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Fig. 1: Inhibition of CDK4/6 induces cell cycle arrest in G1 phase.
Fig. 2: Different cell fates caused by CDK4/6 inhibitors influence treatment outcome.
Fig. 3: Sequential treatment with CDK4/6 inhibitors and senolytics.

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Acknowledgements

Grants from CRUK (C15075/A28647) and core support from MRC (MC_U120085810) funded this research in J. Gil’s Laboratory. VW was funded by the German Cancer Aid Mildred-Scheel Postdoc Program.

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  1. MRC London Institute of Medical Sciences (LMS), Du Cane Road, London, W12 0NN, UK

    Verena Wagner & Jesús Gil

  2. Institute of Clinical Sciences (ICS), Faculty of Medicine, Imperial College London, Du Cane Road, London, W12 0NN, UK

    Verena Wagner & Jesús Gil

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JG has acted as a consultant for Unity Biotechnology and Geras Bio and Merck KGaA, owns equity in Unity Biotechnology and Geras Bio, and is a named inventor in an MRC patent related to senolytic therapies.

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Wagner, V., Gil, J. Senescence as a therapeutically relevant response to CDK4/6 inhibitors. Oncogene 39, 5165–5176 (2020). https://doi.org/10.1038/s41388-020-1354-9

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  • DOI: https://doi.org/10.1038/s41388-020-1354-9

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