title: Achievements and challenges of molecular targeted therapy in melanoma.
abstract: The treatment of melanoma has been revolutionized over the past decade with the development of effective molecular and immune targeted therapies. The great majority of patients with melanoma have mutations in oncogenes that predominantly drive signaling through the mitogen activated protein kinase (MAPK) pathway. Analytic tools have been developed that can effectively stratify patients into molecular subsets based on the identification of mutations in oncogenes and/or tumor suppressor genes that drive the MAPK pathway. At the same time, potent and selective inhibitors of mediators of the MAPK pathway such as RAF, MEK, and ERK have become available. The most dramatic example is the development of single-agent inhibitors of BRAF (vemurafenib, dabrafenib, encorafenib) and MEK (trametinib, cobimetinib, binimetinib) for patients with metastatic BRAFV600-mutant melanoma, a subset that represents 40% to 50% of patients with metastatic melanoma. More recently, the elucidation of mechanisms underlying resistance to single-agent BRAF inhibitor therapy led to a second generation of trials that demonstrated the superiority of BRAF inhibitor/MEK inhibitor combinations (dabrafenib/trametinib; vemurafenib/cobimetinib) compared to single-agent BRAF inhibitors. Moving beyond BRAFV600 targeting, a number of other molecular subsets--such as mutations in MEK, NRAS, and non-V600 BRAF and loss of function of the tumor suppressor neurofibromatosis 1 (NF1)--are predicted to respond to MAPK pathway targeting by single-agent pan-RAF, MEK, or ERK inhibitors. As these strategies are being tested in clinical trials, preclinical and early clinical trial data are now emerging about which combinatorial approaches might be best for these patients.
authors.affiliation: From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Ryan
authors.initials: R
authors.lastname: Sullivan
authors.affiliation: From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Patricia
authors.initials: P
authors.lastname: LoRusso
authors.affiliation: From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Scott
authors.initials: S
authors.lastname: Boerner
authors.affiliation: From the Massachusetts General Hospital Cancer Center, Boston, MA; Yale Cancer Center, New Haven, CT; Yale University, New Haven, CT; University Hospital of Zurich, Zurich, Switzerland.
authors.forename: Reinhard
authors.initials: R
authors.lastname: Dummer
mesh_terms: D000818:Animals; D055808:Drug Discovery; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D023281:Genomics / Q000379:methods; D006801:Humans; D008545:Melanoma / Q000175:diagnosis / Q000209:etiology / Q000628:therapy*; D025202:Molecular Diagnostic Techniques; D058990:Molecular Targeted Therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf