CRAF dimerization with ARAF regulates KRAS-driven tumor growth

KRAS, which is mutated in ∼30% of all cancers, activates the RAF-MEK-ERK signaling cascade. CRAF is required for growth of KRAS mutant lung tumors, but the requirement for CRAF kinase activity is unknown. Here, we show that subsets of KRAS mutant tumors are dependent on CRAF for growth. Kinase-dead but not dimer-defective CRAF rescues growth inhibition, suggesting that dimerization but not kinase activity is required. Quantitative proteomics demonstrates increased levels of CRAF:ARAF dimers in KRAS mutant cells, and depletion of both CRAF and ARAF rescues the CRAF-loss phenotype. Mechanistically, CRAF depletion causes sustained ERK activation and induction of cell-cycle arrest, while treatment with low-dose MEK or ERK inhibitor rescues the CRAF-loss phenotype. Our studies highlight the role of CRAF in regulating MAPK signal intensity to promote tumorigenesis downstream of mutant KRAS and suggest that disrupting CRAF dimerization or degrading CRAF may have therapeutic benefit. [Display omitted] •CRAF depletion inhibits tumor growth but not ERK signaling in KRAS mutant cells•CRAF kinase domain dimerization and not kinase activity is essential for tumorigenesis•Quantitative proteomics reveal increased levels of CRAF:ARAF versus CRAF:BRAF dimers•ARAF dimers promote ERK signaling upon CRAF loss, leading to cell-cycle arrest Venkatanarayan et al. demonstrate that the CRAF kinase domain and not kinase activity is essential for KRAS-driven tumorigenesis. Quantitative proteomics identify increased levels of CRAF:ARAF dimers in KRAS mutant cells. CRAF loss or dimer disruption results in dysregulated ERK activation and cell-cycle arrest.