Krasloss of heterozygosity promotes MAPK dependent pancreatic ductal adenocarcinoma and induces therapeutic sensitivity

Abstract

AbstractPancreatic cancer is characterised by the prevalence of oncogenic mutations inKRAS. Previous studies have reported that alteredKrasgene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenicKRASmutation is well characterised, the relevance of the partnering wild-typeKRASallele in pancreatic cancer is less well understood and controversial. Usingin vivomouse modelling of pancreatic cancer, we demonstrate that wild-typeKrasrestrains the oncogenic impact of mutantKras, and drastically impacts bothKras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-typeKrasincreases oncogenicKrassignalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulatedMyclevels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-typeKrassensitisesKrasmutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-typeKrasduring pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.