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

ABSTRACT: 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 KP

SUBMITTER: Fey SK 

PROVIDER: S-EPMC11733531 | biostudies-literature | 2025 Jan

REPOSITORIES: biostudies-literature