KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency

Samah W. Awwad (), Colm Doyle, Josie Coulthard, Aldo S. Bader, Nadia Gueorguieva, Simon Lam, Vipul Gupta, Rimma Belotserkovskaya, Tuan-Anh Tran, Shankar Balasubramanian and Stephen P. Jackson ()
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Samah W. Awwad: University of Cambridge
Colm Doyle: University of Cambridge
Josie Coulthard: University of Cambridge
Aldo S. Bader: University of Cambridge
Nadia Gueorguieva: University of Cambridge
Simon Lam: University of Cambridge
Vipul Gupta: University of Cambridge
Rimma Belotserkovskaya: University of Cambridge
Tuan-Anh Tran: University of Cambridge
Shankar Balasubramanian: University of Cambridge
Stephen P. Jackson: University of Cambridge

Nature Communications, 2025, vol. 16, issue 1, 1-16

Abstract: Abstract ATR plays key roles in cellular responses to DNA damage and replication stress, a pervasive feature of cancer cells. ATR inhibitors (ATRi) are in clinical development for treating various cancers, including those with high replication stress, such as is elicited by ARID1A deficiency, but the cellular mechanisms that determine ATRi efficacy in such backgrounds are unclear. Here, we have conducted unbiased genome-scale CRISPR screens in ARID1A-deficient and proficient cells treated with ATRi. We found that loss of transcription factor KLF5 has severe negative impact on fitness of ARID1A-deficient cells while hypersensitising ARID1A-proficient cells to ATRi. KLF5 loss induced replication stress, DNA damage, increased DNA-RNA hybrid formation, and genomic instability upon ATR inhibition. Mechanistically, we show that KLF5 protects cells from replication stress, at least in part through regulating BRD4 recruitment to chromatin. Overall, our work identifies KLF5 as a potential target for eradicating ARID1A-deficient cancers.

Date: 2025
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DOI: 10.1038/s41467-024-55637-5

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