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

Pancreatic 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 ( ). Personalized medicine approaches tailored toward patients' mutations would improve patients' outcome. To identify novel vulnerabilities of -deficient pancreatic cancer, we generated isogenic -deficient murine pancreatic cancer cell lines and performed high-throughput drug screens. High-throughput drug screening revealed that -deficient cells are sensitive to Bromodomain and Extraterminal Motif (BET) inhibitors, suggesting that BET inhibition might be a potential therapeutic approach. We found that deficiency increased autophagic flux, which was further enhanced by BET inhibition in -deficient pancreatic cancer cells, resulting in autophagy-dependent cell death. Our data suggests that BET inhibition can be a novel therapeutic strategy for -deficient pancreatic cancer.