New article in Molecular Cell for de Bruin Lab

A new research article in Molecular Cell for the de Bruin Lab reveals exciting developments in cancer biology, with implications on the therapeutic potential of cell cycle inhibitors for cancer treatment. Read a feature on this and related studies published in the November 16 issue of Molecular Cell.

Wilson GA, et al. Active growth signaling promotes senescence and cancer cell sensitivity to CDK7 inhibition. Molecular Cell, VOLUME 83, ISSUE 22, P4078-4092.E6, NOVEMBER 16, 2023. DOI:https://doi.org/10.1016/j.molcel.2023.10.017

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.