title: Microenvironment-Driven Resistance to BRAF Inhibition Comes of Age.
abstract: Increasingly comprehensive observations indicate that the tumor microenvironment contributes to drug resistance toward small molecule inhibitors. Fedorenko et al. describe a role for fibroblasts in creating a favorable niche for melanoma cell survival if treated with the BRAF inhibitor vemurafenib. TGF-β released by vemurafenib-treated melanoma cells stimulated fibroblasts for increased α-smooth muscle actin, neuregulin (NRG), and fibronectin expression. Off-target effects of vemurafenib led to paradoxical secretion of hepatocyte growth factor (HGF) by fibroblasts. Combined inhibition of BRAF/MET/HER kinases was insufficient to reverse the protective effect of the fibroblasts, whereas reversal was achieved by combined BRAF/PI3K inhibition. A thorough understanding of the complex spatiotemporal interactions in tumor microenvironments holds promise for improved targeting using combination therapies in patients with melanoma.
authors.affiliation: Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia.
authors.forename: Dinoop Ravindran
authors.initials: DR
authors.lastname: Menon
authors.affiliation: Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia; The University of Queensland, The University of Queensland Diamantina Institute, Translational Research Institute, Brisbane, Australia. Electronic address: h.schaider@uq.edu.au.
authors.forename: Helmut
authors.initials: H
authors.lastname: Schaider
mesh_terms: D006801:Humans; D008545:Melanoma / Q000188:drug therapy*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors*
chemical_list: D047428:Protein Kinase Inhibitors; D048493:Proto-Oncogene Proteins B-raf