Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition.

Autor:	Wilson GA; Laboratory for Molecular Cell Biology, University College London, London, UK., Vuina K; Laboratory for Molecular Cell Biology, University College London, London, UK., Sava G; Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, UK., Huard C; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Meneguello L; Laboratory for Molecular Cell Biology, University College London, London, UK; UCL Cancer Institute, University College London, London, UK., Coulombe-Huntington J; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Department of Bioengineering, McGill University, Montréal, QC, Canada., Bertomeu T; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada., Maizels RJ; Laboratory for Molecular Cell Biology, University College London, London, UK., Lauring J; Janssen Research and Development, the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD, USA., Kriston-Vizi J; Laboratory for Molecular Cell Biology, University College London, London, UK., Tyers M; Institute for Research in Immunology and Cancer, Université de Montréal, Montréal, QC, Canada; Hospital for Sick Children, University of Toronto, Toronto, ON, Canada., Ali S; Division of Cancer, Department of Surgery & Cancer, Imperial College London, London, UK., Bertoli C; Laboratory for Molecular Cell Biology, University College London, London, UK. Electronic address: c.bertoli@ucl.ac.uk., de Bruin RAM; Laboratory for Molecular Cell Biology, University College London, London, UK; UCL Cancer Institute, University College London, London, UK. Electronic address: r.debruin@ucl.ac.uk.
Jazyk:	angličtina
Zdroj:	Molecular cell [Mol Cell] 2023 Nov 16; Vol. 83 (22), pp. 4078-4092.e6. Date of Electronic Publication: 2023 Nov 16.
DOI:	10.1016/j.molcel.2023.10.017
Abstrakt:	Tumor growth is driven by continued cellular growth and proliferation. Cyclin-dependent kinase 7's (CDK7) role in activating mitotic CDKs and global gene expression makes it therefore an attractive target for cancer therapies. However, what makes cancer cells particularly sensitive to CDK7 inhibition (CDK7i) remains unclear. Here, we address this question. We show that CDK7i, by samuraciclib, induces a permanent cell-cycle exit, known as senescence, without promoting DNA damage signaling or cell death. A chemogenetic genome-wide CRISPR knockout screen identified that active mTOR (mammalian target of rapamycin) signaling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signaling correlates with sensitivity in cancer cell lines. Reverting a growth-promoting mutation in PIK3CA to wild type decreases sensitivity to CDK7i. Our work establishes that enhanced growth alone promotes CDK7i sensitivity, providing an explanation for why some cancers are more sensitive to CDK inhibition than normally growing cells. Competing Interests: Declaration of interests S.A. is an inventor on a patent describing samuraciclib, which is licensed to Carrick Therapeutics Ltd. S.A. has received royalties from and has share ownership in Carrick Therapeutics. J.L. is currently a full-time employee of and owns stock in Janssen Research and Development and is entitled to receive royalty payments for commercial use of cell lines described in this work under a licensing agreement between Johns Hopkins University and Horizon Discovery, Ltd. (Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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