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Published on: May 27, 2021
KLF5 loss sensitizes cells to ATR inhibition and is synthetic lethal with ARID1A deficiency
Samah W Awwad1,2, Colm Doyle3, Josie Coulthard3
1Cancer Research UK Cambridge Institute, University of Cambridge, Cambridge, UK. samah.diab@cruk.cam.ac.uk.
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.
Insights
Loss of KLF5 protein severely impacts ARID1A-deficient cancer cells while sensitizing proficient cells to ATR inhibitors (ATRi). This suggests KLF5 is a potential therapeutic target for ARID1A-deficient cancers.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- ATR inhibitors (ATRi) show promise for cancers with high replication stress, like those with ARID1A deficiency.
- Mechanisms governing ATRi efficacy in ARID1A-deficient cancers remain unclear.
Purpose of the Study:
- To identify cellular mechanisms determining ATRi efficacy in ARID1A-deficient versus proficient cancer cells.
- To uncover potential therapeutic targets for ARID1A-deficient cancers.
Main Methods:
- Genome-scale CRISPR screens were performed on ARID1A-deficient and proficient cells treated with ATR inhibitors.
- Investigated the impact of KLF5 loss on cellular fitness, replication stress, DNA damage, and DNA-RNA hybrids.
Main Results:
- Loss of transcription factor KLF5 negatively impacts ARID1A-deficient cell fitness.
- KLF5 loss hypersensitizes ARID1A-proficient cells to ATRi, inducing replication stress and DNA damage.
- KLF5 regulates BRD4 recruitment, protecting against replication stress.
Conclusions:
- KLF5 is identified as a key factor influencing ATRi efficacy.
- KLF5 represents a potential therapeutic target for eradicating ARID1A-deficient cancers.
