MECHANISM OF DRUG RESISTANCE IN PANCREATIC CANCER

Abstract

Pancreatic cancer is an aggressive cancer associated with a dismal prognosis. PORCN inhibitors show efficacy in pre-clinical models of Wnt-driven pancreatic cancer due to inactivating mutations in RNF43. Several PORCN inhibitors are undergoing clinical trials. However, both intrinsic and acquired resistance to PORCN inhibitors were observed in some RNF43-mutant pancreatic cancer lines. In this study, we performed an in vivo CRISPR loss-of-function screen in a RNF43-mutant pancreatic cancer xenograft model to identify novel druggable vulnerabilities and drug resistance mechanisms. We found that PI3K/mTOR inhibitors and PORCN inhibitor synergistically suppressed Wnt-driven pancreatic cancer growth due to enhanced cell cycle arrest. And mutations in certain epigenetic factors led to resistance to PORCN inhibitors.