This study investigates the mechanism by which kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression in melanoma. The authors found that BRAF inhibitors, such as sorafenib and 885-A, induce BRAF binding to CRAF in RAS mutant cells, leading to CRAF activation and subsequent MEK-ERK signaling. This activation is not observed in BRAF mutant cells, where BRAF is inactive and does not bind to CRAF. The study also demonstrates that kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma in mice, providing strong evidence for their functional interaction. These findings highlight the importance of understanding pathway signaling in clinical practice and the need to genotype tumors before administering BRAF-selective drugs to identify patients who may respond or experience adverse effects. The study suggests that BRAF-selective inhibitors should not be used in patients with RAS mutant tumors to avoid accelerating tumor growth.This study investigates the mechanism by which kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression in melanoma. The authors found that BRAF inhibitors, such as sorafenib and 885-A, induce BRAF binding to CRAF in RAS mutant cells, leading to CRAF activation and subsequent MEK-ERK signaling. This activation is not observed in BRAF mutant cells, where BRAF is inactive and does not bind to CRAF. The study also demonstrates that kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma in mice, providing strong evidence for their functional interaction. These findings highlight the importance of understanding pathway signaling in clinical practice and the need to genotype tumors before administering BRAF-selective drugs to identify patients who may respond or experience adverse effects. The study suggests that BRAF-selective inhibitors should not be used in patients with RAS mutant tumors to avoid accelerating tumor growth.