Fournier, L.-A.; Kalantari, F.; Wells, J. P.; Lee, J. S.; Trigo-Gonzalez, G.; Moksa, M. M.; Smith, T.; White, J.; Shanks, A.; Wang, L.; Su, E.; Wang, Y.; Huntsman, D. G.; Hirst, M.; Stirling, P. C.

ARID1A is the core DNA binding subunit of the BAF chromatin remodeling complex and is mutated in about ~8% of all cancers. The frequency of ARID1A loss varies between cancer subtypes, with clear cell ovarian carcinoma (CCOC) presenting the highest incidence at >50% of cases. Despite a growing understanding of the consequences of ARID1A-loss in cancer, there remains limited targeted therapeutic options for ARID1A-deficient cancers. Using a genome-wide CRISPR screening approach, we identify KEAP1 as a synthetic lethal partner of ARID1A in CCOC. Depletion or chemical inhibition of KEAP1 results in the selective killing of ARID1A-KO cells. While we confirm that KEAP1-NRF2 signalling is dysregulated in ARID1A-KO cells, we suggest that this synthetic lethality is not due to aberrant NRF2 signalling. Rather, we find that KEAP1 perturbation exacerbates genome instability phenotypes associated with ARID1A-deficiency. We also confirm the selective killing of ARID1A-KO cells by the KEAP1 inhibitor AI-1 in edited primary endometrial epithelial cells and organoids. Together, our findings uncover a novel therapeutic avenue for the treatment of cancers harboring ARID1A mutations.