Abstract
With the increasing volume of genetic melanoma profiling, key oncogenic driver mutations have attracted substantial attention as therapeutic targets. Chief among these are BRAF and KIT. Since BRAF mutations occur in about half of all melanomas, BRAF pathway inhibition has attracted the bulk of therapeutic attention. The discovery of BRAF mutations in cutaneous melanomas led to considerable research into the role of BRAF/MEK/ERK signaling and its role in melanomagenesis. In parallel, drug discovery efforts targeting BRAF, MEK, and ERK led to promising therapeutic candidates. Single-agent BRAF inhibitors showed strong efficacy in metastatic melanoma patients, effectively transforming the treatment for BRAF-mutant cutaneous melanoma patients. MEK inhibitors also showed efficacy as single agents, but the combination of BRAF and MEK inhibitors was clearly superior to either single-agent treatment. ERK inhibitors are currently undergoing clinical development. KIT mutations are primarily found in acral and mucosal melanomas, and several KIT inhibitors have been tested in KIT-mutant melanoma clinical trials; so far none have been approved by regulatory agencies. The challenge for KIT inhibitors may lie in the rarity and diversity of KIT genetic mutations. This chapter explores the biology of BRAF- and KIT-mutant melanoma cells and describes discovery of therapeutic candidates and reviews their role in clinical care.
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Bollag, G., Flaherty, K.T. (2018). Principles of Targeted Therapy. In: Fisher, D., Bastian, B. (eds) Melanoma. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7322-0_35-1
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