ArticleNature communications2025
KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency.
Article in Nature communications, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
What it found
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The trial behind it
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Who cites it
9 citing papers in PubMed.
- BRD4: From molecular understanding to therapeutics development.Molecular cell · 2026Review
- ATR activity regulates DNA replication and RNA polymerase II transcription during S-phase.iScience · 2026Article
- Targeting epigenetic regulators induces transcription-replication conflicts to overcome ATR inhibitor resistance.Nucleic acids research · 2026Article
- An SP110-SP100 axis is a critical regulator of promyelocytic leukaemia body dynamics and mitotic fidelity.Nature cell biology · 2026Article
- KLF5 controls subtype-independent highly interactive enhancers in pancreatic cancer to regulate cell survival.Science advances · 2026Article
- Loss of CTLH component MAEA impairs DNA repair and replication and leads to developmental delay.EMBO molecular medicine · 2026Article
- Synthetic lethality in cancer therapy: Mechanisms, models and clinical translation for overcoming therapeutic resistance.Clinical and translational medicine · 2026Review
- Epigenetic synthetic lethality as a cancer therapeutic strategy: synergy of experimental and computational approaches.Epigenomics · 2025Review
- Struct2SL: Synthetic lethality prediction based on AlphaFold2 structure information and Multilayer Perceptron.Computational and structural biotechnology journal · 2025Article
Corrections and comments
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Authors and funding
11 authors.
Funding
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.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.