A study reveals that kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. The research shows that BRAF inhibition in the presence of oncogenic RAS leads to CRAF activation and MEK-ERK signaling, which is not observed when BRAF is inhibited alone. Kinase-dead BRAF mimics the effects of BRAF-selective drugs and, when combined with oncogenic RAS, induces melanoma in mice. The findings highlight the importance of understanding pathway signaling in clinical practice and the need for genotyping tumors before administering BRAF-selective drugs to identify patients likely to respond or experience adverse effects. The RAS-ERK signaling pathway is crucial in melanoma, with mutations in BRAF, NRAS, and KRAS being common. While most BRAF mutations are activating, some are non-functional but still present in tumors. The study shows that BRAF inhibitors can activate CRAF and MEK-ERK signaling in RAS mutant cells, even when BRAF is inactive. This activation is dependent on the presence of oncogenic RAS and is not observed when BRAF is inhibited alone. The study also demonstrates that kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma in mice. This cooperation is significant, as it suggests a functional interaction between these two proteins. The findings have important implications for the use of BRAF-selective drugs in clinical practice, emphasizing the need for careful patient selection and monitoring. The study provides insights into the mechanisms of BRAF-mediated signaling and highlights the potential for resistance to RAF-targeting drugs. It also underscores the importance of understanding signaling networks to develop effective therapeutic strategies. The research has important clinical implications, suggesting that BRAF-selective inhibitors should not be used in patients with RAS mutant tumors due to the risk of accelerating tumor growth. The study also raises questions about the role of CRAF in resistance to RAF-targeting drugs and the potential for BRAF-mediated activation of CRAF to promote tumor growth.A study reveals that kinase-dead BRAF and oncogenic RAS cooperate to drive tumor progression through CRAF. The research shows that BRAF inhibition in the presence of oncogenic RAS leads to CRAF activation and MEK-ERK signaling, which is not observed when BRAF is inhibited alone. Kinase-dead BRAF mimics the effects of BRAF-selective drugs and, when combined with oncogenic RAS, induces melanoma in mice. The findings highlight the importance of understanding pathway signaling in clinical practice and the need for genotyping tumors before administering BRAF-selective drugs to identify patients likely to respond or experience adverse effects. The RAS-ERK signaling pathway is crucial in melanoma, with mutations in BRAF, NRAS, and KRAS being common. While most BRAF mutations are activating, some are non-functional but still present in tumors. The study shows that BRAF inhibitors can activate CRAF and MEK-ERK signaling in RAS mutant cells, even when BRAF is inactive. This activation is dependent on the presence of oncogenic RAS and is not observed when BRAF is inhibited alone. The study also demonstrates that kinase-dead BRAF and oncogenic RAS cooperate to induce melanoma in mice. This cooperation is significant, as it suggests a functional interaction between these two proteins. The findings have important implications for the use of BRAF-selective drugs in clinical practice, emphasizing the need for careful patient selection and monitoring. The study provides insights into the mechanisms of BRAF-mediated signaling and highlights the potential for resistance to RAF-targeting drugs. It also underscores the importance of understanding signaling networks to develop effective therapeutic strategies. The research has important clinical implications, suggesting that BRAF-selective inhibitors should not be used in patients with RAS mutant tumors due to the risk of accelerating tumor growth. The study also raises questions about the role of CRAF in resistance to RAF-targeting drugs and the potential for BRAF-mediated activation of CRAF to promote tumor growth.