This study investigates the mechanisms of resistance to RAF inhibition in melanoma using tumor genomic profiling. Researchers analyzed a melanoma tumor that developed resistance to the RAF inhibitor PLX4032 after an initial response. They performed targeted, massively parallel sequencing of 138 cancer genes and identified an activating mutation in the MEK1 gene (MEK1^C121S) that was absent in the pretreatment tumor. This mutation increased kinase activity and conferred resistance to both RAF and MEK inhibition in vitro. The study suggests that MEK1^C121S or similar mutations may confer resistance to combined MEK/RAF inhibition. These findings provide a framework for understanding acquired resistance to kinase inhibition and demonstrate the utility of emerging genomic technologies in personalized cancer medicine. The study also explores the broader mechanisms of resistance to kinase inhibitors, including secondary mutations, gene amplification, and activation of bypass pathways. In melanoma, resistance to RAF inhibition is often due to reactivation of the oncogenic pathway rather than engagement of new oncogenic pathways. The study highlights the importance of understanding these mechanisms to develop more effective treatments. The research underscores the role of MEK1 mutations in resistance to RAF inhibition, particularly the MEK1^C121S mutation, which was found in the resistant tumor. This mutation was shown to confer resistance to both RAF and MEK inhibitors. The study also identifies other potential resistance mutations in MEK1, which may emerge in future sequencing studies of patients with relapsing melanoma. The findings have important therapeutic implications, suggesting that combination therapies targeting both the primary oncogene dependency and bypass mechanisms may be necessary to overcome resistance. The study also highlights the challenges in diagnosing and managing resistance, emphasizing the need for systematic genetic profiling of tumors to identify clinically relevant resistance mechanisms. Overall, the study provides valuable insights into the mechanisms of resistance to targeted therapies and highlights the potential of genomic profiling in personalized cancer medicine.This study investigates the mechanisms of resistance to RAF inhibition in melanoma using tumor genomic profiling. Researchers analyzed a melanoma tumor that developed resistance to the RAF inhibitor PLX4032 after an initial response. They performed targeted, massively parallel sequencing of 138 cancer genes and identified an activating mutation in the MEK1 gene (MEK1^C121S) that was absent in the pretreatment tumor. This mutation increased kinase activity and conferred resistance to both RAF and MEK inhibition in vitro. The study suggests that MEK1^C121S or similar mutations may confer resistance to combined MEK/RAF inhibition. These findings provide a framework for understanding acquired resistance to kinase inhibition and demonstrate the utility of emerging genomic technologies in personalized cancer medicine. The study also explores the broader mechanisms of resistance to kinase inhibitors, including secondary mutations, gene amplification, and activation of bypass pathways. In melanoma, resistance to RAF inhibition is often due to reactivation of the oncogenic pathway rather than engagement of new oncogenic pathways. The study highlights the importance of understanding these mechanisms to develop more effective treatments. The research underscores the role of MEK1 mutations in resistance to RAF inhibition, particularly the MEK1^C121S mutation, which was found in the resistant tumor. This mutation was shown to confer resistance to both RAF and MEK inhibitors. The study also identifies other potential resistance mutations in MEK1, which may emerge in future sequencing studies of patients with relapsing melanoma. The findings have important therapeutic implications, suggesting that combination therapies targeting both the primary oncogene dependency and bypass mechanisms may be necessary to overcome resistance. The study also highlights the challenges in diagnosing and managing resistance, emphasizing the need for systematic genetic profiling of tumors to identify clinically relevant resistance mechanisms. Overall, the study provides valuable insights into the mechanisms of resistance to targeted therapies and highlights the potential of genomic profiling in personalized cancer medicine.