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posted on 2023-12-21, 14:20 authored by Siobhan O'Brien, Tajinder Ubhi, Lucie Wolf, Krishna Gandhi, Sichun Lin, Naz Chaudary, Neesha C. Dhani, Michael Milosevic, Grant W. Brown, Stephane Angers Loss of control at S–G2 transition induces sensitivity to ATR inhibitor. A, Schematic representation of chemogenomic CRISPR screen in HPAF-II FBXW7−/− cells using an LD50 dose of AZD6738. B, Results of chemogenomic screen ranked by Z-score generated through DrugZ. C, Immunofluorescence of HPAF-II wild-type and FBXW7−/− cells treated or untreated with AZD6738 and stained for phosphorylated histone H3. Representative images of three independent replicates, scale bar is 50 µm. D, Quantification of C, mean ± SEM, two-way ANOVA. E, Immunofluorescence of HPAF-II wild-type and FBXW7−/− cells during anaphase, representative images of three independent replicates, scale bar is 10 µm. F, Quantification of E, 15 cells per replicate per treatment were imaged. Mean ± SEM, two-way ANOVA.
Funding
Gouvernement du Canada | Canadian Institutes of Health Research (IRSC)
CCS | Canadian Cancer Society Research Institute (CCSRI)
History
ARTICLE 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 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.
We have elucidated the synthetic lethal interactions between FBXW7 mutation and DNA damage response genes, and highlighted the potential of ATR inhibitors as targeted therapies for cancers harboring FBXW7 alterations.
