BRAF targets in melanoma. Biological mechanisms, resistance, and drug discovery. Cancer drug discovery and development. Volume 82. Ed. Ryan J. Sullivan. Springer (2015)

Constitutive activation of the mitogen activated protein-kinase (MAPK) pathway drives growth and progression in most melanomas of which 40–50% harbor BRAFV600 mutations. The discovery of small molecule inhibitors which suppress MAPK signaling has represented a major step forward in melanoma therapeutics. Pathway inhibition has now been achieved by targeting different levels of the pathway and has efficacy in advanced melanoma through direct targeting of mutant BRAF and blockade of its downstream signaling partner, MEK. Two selective inhibitors of BRAF (vemurafenib, dabrafenib) and one MEK inhibitor (trametinib) are now approved for clinical use and several other agents are advancing in the developmental pipeline. These targeted therapies induce rapid tumor regressions in many patients and improve clinical outcomes in comparison to cytotoxic chemotherapy based on progression-free and overall survival. Acquired resistance remains the significant problem, although progression can be forestalled by combination therapy. In this chapter, we will review the clinical utility of these small molecule inhibitors in BRAFV600 mutant melanoma, focusing on approved agents but also briefly discussing an early BRAF inhibitor and newer, experimental agents.

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