Novel inhibitors in the treatment of metastatic melanoma.
Metastatic melanoma continues to be a difficult disease to treat. Recent efforts have focused on developing novel, target-directed therapeutic agents. In this review, we discuss the RAS-RAF-MAP kinase and the RAS-PI3K-AKT pathway in detail, as up to 80% of cutaneous melanomas exhibit a BRAF mutation. The preclinical and clinical data regarding BRAF inhibition is reviewed. Other potential targets in these pathways are also discussed. Preclinical data have recently emerged, suggesting that the following subsets of patients have a lower frequency of BRAF mutations: acral, mucosal and cutaneous melanomas with chronic sun-induced damage. These lesions have a higher frequency of KIT mutations. However, cutaneous melanomas without chronic sun damage have a higher frequency of BRAF mutations and are not noted to have KIT mutations. It is possible that the appropriate subset of patients may respond differently to available targeted therapies and clinical trials are in development to assess the utility of KIT inhibition in these patients.
Kalinsky
Kevin
K
Tufts-New England Medical Center, Cancer Center & the Division of Hematology/Oncology, Boston, MA 02111, USA. kkalinsky@tufts-nemc.org
Haluska
Frank G
FG
D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D008545:Melanoma / Q000188:drug therapy* / Q000556:secondary; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000473:pathology; D018631:ras Proteins / Q000502:physiology
D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D017346:Protein Serine-Threonine Kinases; D048493:Proto-Oncogene Proteins B-raf; D018631:ras Proteins