MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival

Abstract

Significance Currently, there is no effective targeted therapy for oncogenic KRAS -driven cancer. We set out to identify RAS effector and stress response genes that critically support KRAS addiction, and therefore could serve as potential targets for KRAS mutant cancer. Using a combinatorial siRNA platform, we systematically interrogated the patterns of oncoeffector dependency in KRAS mutant and WT colorectal and pancreatic cancer cell lines and in normal cell lines. We found that RAF kinases are the major KRAS oncoeffectors and that cotargeting BRAF and CRAF kinases together with the autophagy E1 ligase ATG7 could efficiently eliminate KRAS mutant cells while minimizing toxicity in normal cells. Our work thus establishes a framework for the rational selection of target combinations for cancer treatment.