Reversal of Resistance in Targeted Therapy of Metastatic Melanoma: Lessons Learned from Vemurafenib (BRAF(V600E)-Specific Inhibitor)

Malignant melanoma is the most aggressive form of skin cancer and has a very low survival rate. Over 50% of melanomas harbor various BRAF mutations with the most common being the V600E. BRAF(V600E) mutation that causes constitutive activation of the MAPK pathway leading to drug-, immune-resistance, apoptosis evasion, proliferation, survival, and metastasis of melanomas. The ATP competitive BRAF(V600E) selective inhibitor, vemurafenib, has shown dramatic success in clinical trials; promoting tumor regression and an increase in overall survival of patients with metastatic melanoma. Regrettably, vemurafenib-resistance develops over an average of six months, which renders melanomas resistant to other therapeutic strategies. Elucidation of the underlying mechanism(s) of acquisition of vemurafenib-resistance and design of novel approaches to override resistance is the subject of intense clinical and basic research. In this review, we summarize recent developments in therapeutic approaches and clinical investigations on melanomas with BRAF(V600E) mutation to establish a new platform for the treatment of melanoma.