title: Acquired resistance to BRAF inhibition can confer cross-resistance to combined BRAF/MEK inhibition.
abstract: Aberrant activation of the BRAF kinase occurs in ∼60% of melanomas, and although BRAF inhibitors have shown significant early clinical success, acquired resistance occurs in most patients. Resistance to chronic BRAF inhibition often involves reactivation of mitogen-activated protein kinase (MAPK) signaling, and the combined targeting of BRAF and its downstream target MAPK/ERK kinase (MEK) may delay or overcome resistance. To investigate the efficacy of combination BRAF and MEK inhibition, we generated melanoma cell clones resistant to the BRAF inhibitor GSK2118436. These BRAF inhibitor-resistant sublines acquired resistance through several distinct mechanisms, including the acquisition of activating N-RAS mutations and increased accumulation of COT1. These alterations uniformly promoted MAPK reactivation and most conferred resistance to MEK inhibition and to the concurrent inhibition of BRAF and MEK. These data indicate that melanoma tumors are likely to develop heterogeneous mechanisms of resistance, many of which will confer resistance to multiple MAPK inhibitory therapies.
authors.affiliation: Westmead Institute for Cancer Research, University of Sydney at Westmead Millennium Institute and Melanoma Institute Australia, Westmead Hospital, Westmead, New South Wales, Australia.
authors.forename: Kavitha
authors.initials: K
authors.lastname: Gowrishankar
authors.forename: Stephanie
authors.initials: S
authors.lastname: Snoyman
authors.forename: Gulietta M
authors.initials: GM
authors.lastname: Pupo
authors.forename: Therese M
authors.initials: TM
authors.lastname: Becker
authors.forename: Richard F
authors.initials: RF
authors.lastname: Kefford
authors.forename: Helen
authors.initials: H
authors.lastname: Rizos
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D011905:Genes, ras; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008545:Melanoma / Q000188:drug therapy* / Q000473:pathology; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors*; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009154:Mutation; D010091:Oximes / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*; D051057:Proto-Oncogene Proteins c-akt / Q000502:physiology
chemical_list: D007093:Imidazoles; D010091:Oximes; D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D020929:Mitogen-Activated Protein Kinase Kinases; C561627:dabrafenib