A new vulnerability to BET inhibition due to enhanced autophagy in BRCA2 deficient pancreatic cancer

Abstract

AbstractPancreatic cancer is one of the deadliest diseases in human malignancies. Among total pancreatic cancer patients, ∼10% of patients are categorized as familial pancreatic cancer (FPC) patients, carrying germline mutations of the genes involved in DNA repair pathways (e.g., BRCA2). Personalized medicine approaches tailored toward patients’ mutations would improve patients’ outcome. To identify novel vulnerabilities ofBRCA2-deficient pancreatic cancer, we generated isogenicBrca2-deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed thatBrca2-deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found thatBRCA2deficiency increased autophagic flux, which was further enhanced by BET inhibition inBrca2-deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy forBRCA2-deficient pancreatic cancer.