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Ref Type Journal Article
PMID (38032106)
Authors O'Brien S, Ubhi T, Wolf L, Gandhi K, Lin S, Chaudary N, Dhani NC, Milosevic M, Brown GW, Angers S
Title FBXW7-loss sensitizes cells to ATR inhibition through induced mitotic catastrophe.
Journal Vol Issue Date Pages Journal Short Title
Cancer research communications 2023 Nov 30 Cancer Res Commun
URL
Abstract Text FBXW7 is a commonly mutated tumor suppressor gene that functions to regulate numerous oncogenes involved in cell cycle regulation. Genome-wide CRISPR fitness screens identified a signature of DNA repair and DNA damage response genes as required for the growth of FBXW7-knockout cells. Guided by these findings, we show that FBXW7 mutant cells have high levels of replication stress, which results in a genotype-specific vulnerability to inhibition of the ATR signaling pathway, as these mutant cells become heavily reliant on a robust S-G2 checkpoint. ATR-inhibition induces an accelerated S-phase, leading to mitotic catastrophe and cell death caused by the high replication stress present in FBXW7-/- cells. In addition, we provide evidence in cell and organoid studies, and mining of publicly available high throughput drug screening efforts, that this genotype-specific vulnerability extends to multiple types of cancer, providing a rational means of identifying responsive patients for targeted therapy.

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