The MAP kinase signal transduction pathway: promising therapeutic targets used in the treatment of melanoma

Abstract

ABSTRACT Introduction Mitogen-activated protein kinase (MAPK) signal transduction pathway inhibition through the use of agents binding to signal cascade kinases BRAF and MEK has become a key treatment strategy of patients with BRAF-mutant, unresectable melanoma. Areas covered Detailed analysis is undertaken of the current data, presenting the efficacy and safety of recently developed therapies targeting BRAF and MEK inhibition in the setting of unresectable melanoma. MAPK signal transduction, translational findings, current phase I, II and III clinical trials, and ongoing studies are explored, including use of MAPK pathway inhibition in the neoadjuvant and adjuvant settings as well as in combination with immunotherapy and other therapies. Expert opinion Inhibition of the MAPK pathway significantly improves response, progression-free survival, disease specific survival, and overall survival for patients with BRAF-mutant, unresectable melanoma. The concurrent administration of BRAF and MEK inhibiting agents improves response rate and outcomes and reduces serious adverse effects, including development of new cutaneous malignancies. Triplet therapy with BRAK/MEK combination and immunotherapy has shown in early results to increase duration of response and may be best used sequentially as opposed to concurrently to avoid treatment limiting toxicities. Current clinical trials will further define these therapies and their impact on treatment of melanoma.