Targeting BRAF in advanced melanoma: a first step toward manageable disease

Abstract

Melanoma is the deadliest form of skin cancer and its incidence has been increasing worldwide. The disease manifests itself as clinically and genetically distinct subgroups, indicating the need for patient-specific diagnostic and treatment tools. The discovery of activating mutations (V600E) in the BRAF kinase in approximately 50% of patients spurred the development of compounds to inhibit aberrant BRAF activity, and the first drug candidate to show promising clinical activity is PLX4032 (also known as RG7204). Most recent clinical data from a phase II trial indicate that PLX4032 causes tumor regression and stabilized disease in >50% of advanced melanoma patients harboring BRAF V600E tumors. These data validate the effectiveness of oncogene-targeted therapy against advanced melanoma and offer hope that the disease can be overcome. However, as melanoma is dynamic and heterogeneous, careful treatment strategies and combination therapies are warranted to obtain long-term clinical effects.

Figure 1

Simplified schematics of the MAPK and PI3K pathways in melanoma and the clinical compounds available for their inhibition. In the absence of BRAF mutations, receptor tyrosine kinases are activated by their ligands and activate RAS and PI3K. RAS then activates the RAF/MEK/ERK signaling cascade which eventually provides survival, proliferation, invasion, and angiogenesis advantages to melanoma tumors. BRAF mutant melanoma cells are sensitive to BRAF inhibitors but resistance can occur via a RAF isoform switch and other compensatory pathways. Combinatorial approaches targeting more than one molecule within one pathway or several pathways simultaneously need to be carefully investigated as potential treatment options for melanomas refractory to BRAF inhibitors. Compounds targeting the MAPK and PI3K pathways, and currently being tested in clinic trials, are indicated.