MAP kinase and autophagy pathways cooperate to maintain RAS mutant cancer cell survival
Menée sur des lignées cellulaires de cancer colorectal et de cancer du pancréas et à l'aide d'une combinaison de petits ARNs interférents, cette étude met en évidence une coopération entre la kinase MAP et des voies d'autophagie pour maintenir en vie les cellules cancéreuses présentant une mutation sur le gène RAS
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.Oncogenic mutations in the small GTPase KRAS are frequently found in human cancers, and, currently, there are no effective targeted therapies for these tumors. Using a combinatorial siRNA approach, we analyzed a panel of KRAS mutant colorectal and pancreatic cancer cell lines for their dependency on 28 gene nodes that represent canonical RAS effector pathways and selected stress response pathways. We found that RAF node knockdown best differentiated KRAS mutant and KRAS WT cancer cells, suggesting RAF kinases are key oncoeffectors for KRAS addiction. By analyzing all 376 pairwise combination of these gene nodes, we found that cotargeting the RAF, RAC, and autophagy pathways can improve the capture of KRAS dependency better than targeting RAF alone. In particular, codepletion of the oncoeffector kinases BRAF and CRAF, together with the autophagy E1 ligase ATG7, gives the best therapeutic window between KRAS mutant cells and normal, untransformed cells. Distinct patterns of RAS effector dependency were observed across KRAS mutant cell lines, indicative of heterogeneous utilization of effector and stress response pathways in supporting KRAS addiction. Our findings revealed previously unappreciated complexity in the signaling network downstream of the KRAS oncogene and suggest rational target combinations for more effective therapeutic intervention.