Wilson, GA;
Vuina, K;
Sava, G;
Huard, C;
Meneguello, L;
Coulombe-Huntington, J;
Bertomeu, T;
... de Bruin, RAM; + view all
(2023)
Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition.
Molecular Cell
, 83
(22)
4078-4092.e6.
10.1016/j.molcel.2023.10.017.
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Abstract
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.
| Type: | Article |
|---|---|
| Title: | Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.molcel.2023.10.017 |
| Publisher version: | https://doi.org/10.1016/j.molcel.2023.10.017 |
| Language: | English |
| Additional information: | © 2023 The Author(s). Published by Elsevier Inc. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/) |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Life Sciences > Lab for Molecular Cell Bio MRC-UCL |
| URI: | https://discovery-pp.ucl.ac.uk/id/eprint/10182011 |
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