title: The GIST of targeted therapy for malignant melanoma.
abstract: The high response rates to the tyrosine kinase inhibitor imatinib in KIT-mutated gastrointestinal stromal tumors (GIST) has led to a paradigm shift in cancer treatment. In a parallel fashion, the field of melanoma is shifting with the utilization of targeted therapy to treat BRAF-mutated melanoma. We reviewed published literature in PubMed on GIST and melanoma, with a focus on both past and current clinical trials. The data presented centers on imatinib, vemurafenib, and most recently dabrafenib, targeting KIT and BRAF mutations and their outcomes in GIST and melanoma. The BRAF(V600E) melanoma mutation, like the KIT exon 11 mutation in GIST, has the highest response to therapy. High response rates with inhibition of KIT in GIST have not been recapitulated in KIT-mutated melanoma. Median time to resistance to targeted agents occurs in ~7 months with BRAF inhibitors and 2 years for imatinib in GIST. In GIST, the development of secondary mutations leads to resistance; however, there have been no similar gatekeeper mutations found in melanoma. Although surgery remains an important component of the treatment of early GIST and melanoma, surgeons will need to continue to define the thresholds and timing for operation in the setting of metastatic disease with improved targeted therapies. Combination treatment strategies may result in more successful clinical outcomes in the management of melanoma in the future.
authors: Department of Surgery, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.
authors: Danielle M
authors: DM
authors: Bello
authors: Ronald P
authors: RP
authors: Dematteo
authors: Charlotte E
authors: CE
authors: Ariyan
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides / Q000009:adverse effects / Q000627:therapeutic use*; D019008:Drug Resistance, Neoplasm; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate; D007211:Indoles / Q000009:adverse effects / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary; D058990:Molecular Targeted Therapy; D009154:Mutation; D010879:Piperazines / Q000009:adverse effects / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics; D011743:Pyrimidines / Q000009:adverse effects / Q000627:therapeutic use*; D013449:Sulfonamides / Q000009:adverse effects / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D007211:Indoles; D010879:Piperazines; D011743:Pyrimidines; D013449:Sulfonamides; D000077484:Vemurafenib; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf