Active growth signalling promotes senescence and cancer cell sensitivity to CDK7 inhibition
Tumour growth is driven by continued cellular growth and proliferation. Cyclin Dependent Kinase 7's (CDK7) role in activating mitotic CDKs and globalgene 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 signalling or cell death. A chemogenetic genome-wide CRISPR knock-out screen identified that active mTOR (mammalian target of rapamycin) signalling promotes samuraciclib-induced senescence. mTOR inhibition decreases samuraciclib sensitivity, and increased mTOR-dependent growth signalling 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. Overall design: Genome-wide CRISPR/Cas9 screen to test for gene deletions that affect fitness in human cells treated with CDK7 inhibitor samuraciclib.