Cancer interception with KRAS inhibitors in preclinical models of pancreatic ductal adenocarcinoma.

Abstract

Transformation of pancreatic epithelial cells to malignant pancreatic ductal adenocarcinoma (PDAC) typically involves the progression of precancerous pancreatic intraepithelial neoplasia (PanINs) bearing oncogenic <i>KRAS</i> mutations. Here, we tested the impact of PDAC interception using either RAS(ON) multiselective or RAS(ON) G12D-selective pharmacological inhibitors [RAS(ON) inhibitors] in mouse models of PDAC. Treatment of PanIN-bearing mice with RAS(ON) inhibitors prompted regression of premalignant lesions that translated into a delay in tumor onset and an increase in overall survival (OS). Long-term interception in tumor-prone mice resulted in a median OS of more than 1 year compared with less than 5 months in nonintercepted control mice (<i>P</i> < 0.0001). Comparing the survival benefits of RAS(ON) inhibition for cancer interception versus RAS(ON) inhibition for cancer treatment, we found that interception provided a greater survival benefit to mice. These findings suggest that a pharmacological approach may reduce premalignant burden and increase survival in PDAC.