TRIP13 protects pancreatic cancer cells against intrinsic and therapy-induced DNA replication stress.

Oncogene activation in normal untransformed cells induces DNA replication stress and creates a dependency on DNA damage response (DDR) mechanisms for cell survival. Different oncogenic stimuli signal via distinct mechanisms in every cancer setting. The DDR is also pathologically reprogrammed and deployed in diverse ways in different cancers. Because mutant KRAS is the driver oncogene in 90% of pancreatic ductal adenocarcinomas (PDACs), here we have investigated DDR mechanisms by which KRAS-induced DNA replication stress is tolerated in normal human pancreatic epithelial cells [human pancreatic nestin-expressing (HPNE) cells]. Using a candidate screening approach, we identify TRIP13 as a KRAS(G12V)-induced messenger RNA that is also expressed at high levels in PDAC relative to normal tissues. Using genetic and pharmacological tools, we show that TRIP13 is necessary to sustain ongoing DNA synthesis and viability specifically in KRAS(G12V)-expressing cells. TRIP13 promotes survival of KRAS(G12V)-expressing HPNE cells in a homologous recombination (HR)-dependent manner. KRAS(G12V)-expressing HPNE cells lacking TRIP13 acquire hallmark HR deficiency phenotypes, including sensitivity to inhibitors of translesion synthesis and poly-ADP ribose polymerase. Established PDAC cell lines are also sensitized to intrinsic DNA damage and therapy-induced genotoxicity following TRIP13 depletion. Taken together, our results expose TRIP13 as an attractive new and therapeutically tractable vulnerability of KRAS-mutant PDAC.