New Drug Combination Strategies in Melanoma: Current Status and Future Directions.

Melanoma is the deadliest form of skin cancer and one of the most difficult cancers to treat. Overall, melanomas have more mutations than any other cancer type. Oncogenic mutations in c-KIT, NRAS and BRAF components of the MAPK pathway have been identified in nearly 90% of cutaneous melanoma and this information has been used to develop small molecules that inhibit their activity. Highly selective BRAF and MEK inhibitors have demonstrated impressive clinical results. However, the short duration of response, the acquired resistance in most cases and the toxicity issues support the rationale for drug combination approaches to improve the outcome of MAPK inhibitors, increase their efficacy, prevent and/or overcome resistance. This review discusses several promising rational combinatorial strategies investigated or could be investigated in clinical studies.