FBXW7-loss Sensitizes Cells to ATR Inhibition Through Induced Mitotic Catastrophe.

ABSTRACT: 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 avai

SUBMITTER: O'Brien S 

PROVIDER: S-EPMC10734389 | biostudies-literature | 2023 Dec

REPOSITORIES: biostudies-literature