Pharmacological Induction of RAS-GTP Confers RAF Inhibitor Sensitivity in KRAS Mutant Tumors

• Published in: Cancer cell Vol. 34; no. 4; pp. 611 - 625.e7
• Main Authors: Yen, Ivana, Shanahan, Frances, Merchant, Mark, Orr, Christine, Hunsaker, Thomas, Durk, Matthew, La, Hank, Zhang, Xiaolin, Martin, Scott E., Lin, Eva, Chan, John, Yu, Yihong, Amin, Dhara, Neve, Richard M., Gustafson, Amy, Venkatanarayan, Avinashnarayan, Foster, Scott A., Rudolph, Joachim, Klijn, Christiaan, Malek, Shiva
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 08.10.2018
• Subjects: BRAF; cancer; Cell Line, Tumor; combination treatment; CRAF; Guanosine Triphosphate - metabolism; Humans; KRAS; MAPK; MEK inhibitors; Mutation - drug effects; Mutation - genetics; Phosphatidylinositol 3-Kinases - drug effects; Phosphatidylinositol 3-Kinases - genetics; PI3K inhibitors; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - drug effects; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins p21(ras) - drug effects; Proto-Oncogene Proteins p21(ras) - genetics; RAF inhibitors; ras Proteins - drug effects; ras Proteins - genetics; RAS-GTP; RAF inhibitors; combination treatment; MEK inhibitors; KRAS; cancer; BRAF; RAS-GTP; CRAF; MAPK; PI3K inhibitors
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccell.2018.09.002

Targeting KRAS mutant tumors through inhibition of individual downstream pathways has had limited clinical success. Here we report that RAF inhibitors exhibit little efficacy in KRAS mutant tumors. In combination drug screens, MEK and PI3K inhibitors synergized with pan-RAF inhibitors through an RAS-GTP-dependent mechanism. Broad cell line profiling with RAF/MEK inhibitor combinations revealed synergistic efficacy in KRAS mutant and wild-type tumors, with KRASG13D mutants exhibiting greater synergy versus KRASG12 mutant tumors. Mechanistic studies demonstrate that MEK inhibition induced RAS-GTP levels, RAF dimerization and RAF kinase activity resulting in MEK phosphorylation in synergistic tumor lines regardless of KRAS status. Taken together, our studies uncover a strategy to rewire KRAS mutant tumors to confer sensitivity to RAF kinase inhibition. [Display omitted] •NRAS but not KRAS mutant tumors are more sensitive to RAF kinase inhibition•Combined RAF-MEK or RAF-PI3K inhibition exhibits synergy in RAS mutant cancers•KRAS-G13D mutant tumors exhibit higher synergy with combined RAF-MEK inhibition•Drug-induced RAF dimers and RAS-GTP levels confer sensitivity to RAF inhibition Yen et al. show that RAF inhibitors have little efficacy against KRAS mutant tumors. MEK inhibition sensitizes the subset of KRAS mutant and wild-type tumors that increase BRAF-CRAF dimerization and RAS-GTP levels upon pan-RAF inhibition. The combination is particularly effective against tumors with KRASG13D.