title: Resistant mechanisms to BRAF inhibitors in melanoma.
abstract: Patients with advanced melanoma have traditionally had very poor prognosis. However, since 2011 better understanding of the biology and epidemiology of this disease has revolutionized its treatment, with newer therapies becoming available. These newer therapies can be classified into immunotherapy and targeted therapy. The immunotherapy arsenal includes inhibitors of CTLA4, PD-1 and PDL-1, while targeted therapy focuses on BRAF and MEK. BRAF inhibitors (vemurafenib, dabrafenib) have shown benefit in terms of overall survival (OS) compared to chemotherapy, and their combination with MEK inhibitors has recently been shown to improve progression-free survival (PFS), compared with monotherapy with BRAF inhibitors. However, almost 20% of patients initially do not respond, due to intrinsic resistance to therapy and, of those who do, most eventually develop mechanisms of acquired resistance, including reactivation of the MAP kinase pathway, persistent activation of receptor tyrosine kinase (RTKS) receptor, activation of phosphatidyinositol-3OH kinase, overexpression of epidermal growth factor receptor (EGFR), and interactions with the tumor microenvironment. Herein we comment in detail on mechanisms of resistance to targeted therapy and discuss the strategies to overcome them.
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain;; Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Badalona, Catalonia, Spain;
authors.forename: José Luís
authors.initials: JL
authors.lastname: Manzano
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain ;
authors.forename: Laura
authors.initials: L
authors.lastname: Layos
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain ;
authors.forename: Cristina
authors.initials: C
authors.lastname: Bugés
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain ;
authors.forename: María
authors.initials: M
authors.lastname: de Los Llanos Gil
authors.affiliation: Medical Oncology Service, Catalan Institute of Oncology (ICO), Germans Trias i Pujol University Hospital, Badalona, Barcelona, Catalonia, Spain ;
authors.forename: Laia
authors.initials: L
authors.lastname: Vila
authors.affiliation: Health Sciences Research Institute of the Germans Trias i Pujol Foundation (IGTP), Badalona, Catalonia, Spain ;
authors.forename: Eva
authors.initials: E
authors.lastname: Martínez-Balibrea
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet de Llobregat, Barcelona, Catalonia, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Martínez-Cardús
keywords: MAP kinase; Melanoma; biomarkers; resistance; targeted therapy