Non-BRAF targeted therapies for melanoma: protein kinase inhibitors in Phase II clinical trials.

INTRODUCTION: Melanoma is one of the most aggressive forms of cutaneous malignancies displaying a substantial mortality rate among the various forms of skin cancers. The management of patients with advanced melanoma poses a significant challenge considering that the disease is refractory to most conventional therapies. AREAS COVERED: This review highlights some of the genes and signaling molecules that are mutated in melanoma patients. The authors also discuss protein kinase inhibitors targeting non-BRAF mutations that are now being evaluated in Phase II clinical trials. EXPERT OPINION: In light of several preclinical and clinical studies, it is clear that targeting single-gene mutations may not provide a desired therapeutic gain in the context of melanoma. Consequently, research will need to focus on rational combinations of novel therapeutic agents targeting multiple genetic aberrations or deregulated pathways to achieve a desired maximum clinical benefit. There is certainly a need for a better understanding of the complex and redundant molecular signatures associated with melanoma development; this would open up new avenues for creating the next generation of targeted and effective therapeutics.