title: Overcoming resistance to BRAF inhibition in BRAF-mutated metastatic melanoma.
abstract: Almost 50% of metastatic melanoma patients harbor a BRAF(V600) mutation and the introduction of BRAF inhibitors has improved their treatment options. BRAF inhibitors vemurafenib and dabrafenib achieved improved overall survival over chemotherapy and have been approved for the treatment of BRAF-mutated metastatic melanoma. However, most patients develop mechanisms of acquired resistance and about 15% of them do not achieve tumor regression at all, due to intrinsic resistance to therapy. Moreover, early adaptive responses limit the initial efficacy of BRAF inhibition, leading mostly to incomplete responses that may favor the selection of a sub-population of resistant clones and the acquisition of alterations that cause tumor regrowth and progressive disease. The purpose of this paper is to review the mechanisms of resistance to therapy with BRAF inhibitors and to discuss the strategies to overcome them based on pre-clinical and clinical evidences.
authors.affiliation: Department of Plastic and Reconstructive Surgery - IRCCS Azienda Ospedaliera Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro - Genova, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Spagnolo
authors.affiliation: Genetics of rare cancers, Department of Internal Medicine and Medical Specialties (DiMI), University of Genoa, Genova, Italy. IRCCS Azienda Ospedaliera Universitaria San Martino IST, Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Ghiorzo
authors.affiliation: Department of Medical Oncology - IRCCS Azienda Ospedaliera Universitaria San Martino - IST - Istituto Nazionale per la Ricerca sul Cancro - Genova, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Queirolo
mesh_terms: D000818:Animals; D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology / Q000627:therapeutic use*; D007211:Indoles / Q000494:pharmacology / Q000627:therapeutic use*; D008545:Melanoma / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D009362:Neoplasm Metastasis; D010091:Oximes / Q000494:pharmacology / Q000627:therapeutic use*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D012008:Recurrence; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D013449:Sulfonamides / Q000494:pharmacology / Q000627:therapeutic use*; D000077484:Vemurafenib
chemical_list: D007093:Imidazoles; D007211:Indoles; D010091:Oximes; D013449:Sulfonamides; D000077484:Vemurafenib; D048493:Proto-Oncogene Proteins B-raf; C561627:dabrafenib