ALDH1A1 Contributes to PARP Inhibitor Resistance via Enhancing DNA Repair in BRCA2^-/- Ovarian Cancer Cells.

Poly (ADP-ribose) polymerase inhibitors are approved to treat recurrent ovarian cancer with BRCA1 or BRCA2 mutations, and as maintenance therapy for recurrent platinum-sensitive ovarian cancer (BRCA wild-type or mutated) after treatment with platinum. However, the acquired resistance against remains a clinical hurdle. Here, we demonstrated that inhibitor (olaparib)-resistant epithelial ovarian cancer (EOC) cells exhibited an elevated aldehyde dehydrogenase (ALDH) activity, mainly contributed by increased expression of ALDH1A1 due to olaparib-induced expression of BRD4, a member of bromodomain and extraterminal (BET) family protein. We also revealed that ALDH1A1 enhanced microhomology-mediated end joining (MMEJ) activity in EOC cells with inactivated BRCA2, a key protein that promotes homologous recombination (HR) by using an intrachromosomal MMEJ reporter. Moreover, NCT-501, an ALDH1A1-selective inhibitor, can synergize with olaparib in killing EOC cells carrying BRCA2 mutation in both in vitro cell culture and the in vivo xenograft animal model. Given that MMEJ activity has been reported to be responsible for Pduanyu37i resistance in HR-deficient cells, we conclude that ALDH1A1 contributes to the resistance to Pduanyu37 inhibitors via enhancing MMEJ in BRCA2^-/- ovarian cancer cells. Our findings provide a novel mechanism underlying Pduanyu37i resistance in BRCA2-mutated EOC cells and suggest that inhibition of ALDH1A1 could be exploited for preventing and overcoming Pduanyu37i resistance in EOC patients carrying BRCA2 mutation.

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