Inactivating BRAF Mutations Modulate RAS–MAPK Signaling

Activating mutations in BRAF are common drivers of tumorigenesis, but inactivating BRAF mutations (termed class 3) also occur frequently in cancer. Yao and colleagues found that class 3 BRAF mutants amplify ERK signaling by binding more tightly to active RAS and dimerizing with and activating wild-type CRAF. Class 3 BRAF mutants were RAS dependent and required coexistent mechanisms to activate RAS despite ERK-dependent feedback. In melanoma, class 3 BRAF mutations coexisted with NF1 or RAS mutations; thus, these tumors are limited to targeted therapy with MEK or ERK inhibitors. In contrast, in other tumors with class 3 BRAF mutations, RAS was driven by receptor tyrosine kinase (RTK) signaling. These tumors are sensitive to inhibition of the RTK that drives RAS, alone or in combination with MEK inhibition, suggesting that therapeutic strategies in tumors with class 3 BRAF mutations depend on the mechanism of RAS activation. In a complementary study, Nieto and colleagues explored the role of the BRAF-inactivating D594A mutation (D631A in mice) in mice with KRAS-driven lung adenocarcinoma. Kinase-dead BRAF accelerated tumor development and reduced survival, an effect that was mediated by the RAF isoform CRAF. Ablating the remaining Braf allele enhanced MAPK signaling, triggering a stress response that resulted in lung damage, club cell transdifferentiation, and intrabronchiolar outgrowths. MEK inhibition rescued lung toxicity, restoring KRAS-driven adenocarcinoma formation. Further, kinase dead BRAF was sufficient to induce lung adenocarcinoma in the absence of Kras mutations, indicating that class 3 BRAF mutations can drive tumorigenesis. Altogether, these studies provide a mechanism by which BRAF inactivating mutations can promote tumorigenesis, indicate that the intensity of MAPK signaling determines the tumor phenotype, and show the dependency of carcinomas with these mutations on RTKs that may be therapeutically targeted.

Yao Z, Yaeger R, Rodrik-Outmezguine VS, Tao A, Torres NM, Chang MT, et al. Tumours with class 3 BRAF mutants are sensitive to the inhibition of activated RAS. Nature 2017;548:234–8.

Nieto P, Ambrogio C, Esteban-Burgos L, Gómez-López G, Blasco MT, Yao Z, et al. A Braf kinase-inactive mutant induces lung adenocarcinoma. Nature 2017;548:239–43.

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