title: Detecting mechanisms of acquired BRAF inhibitor resistance in melanoma.
abstract: (V600)BRAF mutation was identified as an ideal target for clinical therapy due to its indispensable roles in supporting melanoma initiation and progression. Despite the fact that BRAF inhibitors (BRAFi) can elicit anti-tumor responses in the majority of treated patients and confer overall survival benefits, acquired drug resistance is a formidable obstacle to long-term management of the disease. Several aberrant events including RTK upregulation, NRAS mutation, mutant BRAF amplification or alternative splicing, and MEK mutation have been reported as acquired BRAFi resistance mechanisms. Clinially, detection of these resistance mechanisms help understand drug response patterns and help guide combinatorial therapeutic strategies. Therefore, quick and accurate diagnosis of the resistant mechanisms in tumor biopsies has become an important starting point for personalized therapy. In this chapter, we review the major acquired BRAFi resistance mechanisms, highlight their therapeutic implications, and provide the diagnostic methods from clinical samples.
authors.affiliation: Department of Medicine, Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
authors.forename: Roger S
authors.initials: RS
authors.lastname: Lo
authors.forename: Hubing
authors.initials: H
authors.lastname: Shi
mesh_terms: D001483:Base Sequence; D004252:DNA Mutational Analysis; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D020558:GTP Phosphohydrolases / Q000235:genetics; D006801:Humans; D008545:Melanoma / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors* / Q000235:genetics; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000201:enzymology* / Q000235:genetics; D015854:Up-Regulation / Q000187:drug effects
chemical_list: D008565:Membrane Proteins; D047428:Protein Kinase Inhibitors; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf; D020929:Mitogen-Activated Protein Kinase Kinases; D020558:GTP Phosphohydrolases; C579846:NRAS protein, human