Inscription à l’infolettre

Publication — IRIC

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

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.

Date de publication
16 novembre 2023
Wilson GA, Vuina K, Sava G, Huard C, Meneguello L, Coulombe-Huntington J, Bertomeu T, Maizels RJ, Lauring J, Kriston-Vizi J, Tyers M, Ali S, Bertoli C, de Bruin RAM
Référence PubMed
Mol Cell 2023;83(22):4078-4092.e6
ID PubMed
Laboratory for Molecular Cell Biology, University College London, London, UK.