KRAS Loss of Heterozygosity Promotes MAPK-Dependent Pancreatic Ductal Adenocarcinoma Initiation and Induces Therapeutic Sensitivity to MEK Inhibition

作者：Sigrid K. Fey, Arafath K. Najumudeen, Dale M. Watt, Laura M. Millett, Catriona A. Ford, Kathryn Gilroy, Robert U. Simpson, Kathy McLay, Rosanna Upstill‐Goddard, David K. Chang, William Clark, Colin Nixon, Joanna L. Birch, Simon T. Barry, Jennifer P. Morton, Andrew D. Campbell, Owen J. Sansom · 发表于：Cancer Research · 年份：2024 · DOI：10.1158/0008-5472.can-23-2709 · 被引用次数：9 · 研究领域：Pancreatic and Hepatic Oncology Research、Caveolin-1 and cellular processes、Cancer Genomics and Diagnostics

Pancreatic cancer is characterized by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered KRAS gene dosage drives progression and metastasis in pancreatic cancer. Whereas the role of oncogenic KRAS mutations is well characterized, the relevance of the partnering wild-type (WT) KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modeling of pancreatic cancer, we demonstrated that WT KRAS restrains the oncogenic impact of mutant KRAS and dramatically impacts both KRAS-mediated tumorigenesis and therapeutic response. Mechanistically, deletion of WT Kras increased oncogenic KRAS signaling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, lack of WT KRAS led to accelerated initiation but delayed tumor progression. These tumors had altered stroma and an enrichment of immunogenic gene signatures. Importantly, loss of WT Kras sensitized Kras mutant tumors to MEK1/2 inhibition though tumors eventually became resistant and then rapidly progressed. This study demonstrates the repressive role of WT KRAS during pancreatic tumorigenesis and highlights the critical impact of the presence of WT KRAS in both tumor progression and therapeutic response in pancreatic cancer. Significance: KRAS allelic status impacts pancreatic cancer progression and has the potential to guide effe...