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Updated: Mar 30, 2026

Characterize Disease-related Mutants of RAF Family Kinases by Using a Set of Practical and Feasible Methods
Published on: July 17, 2019
Microenvironment-Driven Resistance to BRAF Inhibition Comes of Age
Dinoop Ravindran Menon1, Helmut Schaider2
1Dermatology Research Centre, Translational Research Institute, School of Medicine, The University of Queensland, Woolloongabba, Queensland, Australia.
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.
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