JUN is a master mediator of resistance to MAPK pathway inhibition in KRAS-mutant pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is often driven by KRAS mutations, but inhibitors targeting the most frequent KRAS substitutions in PDAC are not yet approved in the clinic. We previously discovered that KRAS-mutant PDAC are sensitive to the combination of SHP2 and ERK inhibitors, recently investigated in the Phase I/Ib clinical trial NCT04916236. Lately, RAS(ON) multi-selective inhibitors have entered clinical development, representing a promise for mono or combination therapies in PDAC. However, resistance may arise even for combination therapies. Here, we aimed at anticipating mechanisms of resistance to SHP2 plus ERK or RAS(ON) multi-selective inhibitors. Through unbiased CRISPR-based screenings, we identified mTOR and JUN hyperactivation as interconnected mechanisms that overcome MAPK suppression. Functional genetic and pharmacological experiments pointed at JUN as the most downstream resistance mediator, and indirect therapeutic target, using MAP2K4 inhibitors. Alterations in the PI3K/AKT/mTOR and JUN pathways may serve as biomarkers for sensitivity/resistance in clinical trials testing MAPK inhibitors combinations in KRAS-mutant PDAC.