Mechanisms of Resistance to BRAF-Targeted Melanoma Therapies

About half of all cutaneous melanomas harbor activating mutations in the BRAF oncogene. Dependence on this pathway makes the tumors vulnerable to BRAF (and downstream MEK) inhibition, and three drug combinations are approved to target this vulnerability in advanced melanomas with BRAFV600 mutations. Responses to BRAF/MEK inhibitors are usually fast, but durability of response can be limited. Five-year data from BRAF/MEK inhibitors show long-term survival benefit for a third of the patients. There is a wide variety of known mechanisms of resistance to BRAF/MEK inhibition, such as mitogen-activated protein kinase reactivation, activation of parallel pathways, alterations in cell-cycle regulation, and non-genetic resistance mechanisms. Strategies that have been explored to overcome these mechanisms include alternative dosing regimens, addition of another kinase inhibitor, and use of anti-PD-1 immunotherapy either in combination or post-relapse on BRAF/MEK inhibitor therapies.