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Kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF

The responses that melanoma cells make to BRAF-elective inhibitors were studied in a murine model and provided a molecular basis for the design of similar drugs. The interaction of kinase-dead BRAF and oncogenic RAS was also studied in vivo. The drugs investigated were sorafenib (a class II inactive confirmation binder), PLX4720 (a class I active conformation binder inhibitor), 885-A (a highly selective BRAF inhibitor) and the selective MEK inhibitor PD184352. BRAF was inactive and not required for MEK/ERK activation in RAS mutant cells, although BRAF inhibitors activate CRAF and MEK in these cells. No strong binding of BRAF to CRAF was seen in A365 cells even in the presence of PD184352, ...