ATR inhibitors as a synthetic lethal therapy for tumours deficient in ARID1A.
Williamson CT., Miller R., Pemberton HN., Jones SE., Campbell J., Konde A., Badham N., Rafiq R., Brough R., Gulati A., Ryan CJ., Francis J., Vermulen PB., Reynolds AR., Reaper PM., Pollard JR., Ashworth A., Lord CJ.
Identifying genetic biomarkers of synthetic lethal drug sensitivity effects provides one approach to the development of targeted cancer therapies. Mutations in ARID1A represent one of the most common molecular alterations in human cancer, but therapeutic approaches that target these defects are not yet clinically available. We demonstrate that defects in ARID1A sensitize tumour cells to clinical inhibitors of the DNA damage checkpoint kinase, ATR, both in vitro and in vivo. Mechanistically, ARID1A deficiency results in topoisomerase 2A and cell cycle defects, which cause an increased reliance on ATR checkpoint activity. In ARID1A mutant tumour cells, inhibition of ATR triggers premature mitotic entry, genomic instability and apoptosis. The data presented here provide the pre-clinical and mechanistic rationale for assessing ARID1A defects as a biomarker of single-agent ATR inhibitor response and represents a novel synthetic lethal approach to targeting tumour cells.