1. Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.
- Author
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Smith MP, Brunton H, Rowling EJ, Ferguson J, Arozarena I, Miskolczi Z, Lee JL, Girotti MR, Marais R, Levesque MP, Dummer R, Frederick DT, Flaherty KT, Cooper ZA, Wargo JA, and Wellbrock C
- Subjects
- Cell Line, Tumor, Drug Resistance, Neoplasm drug effects, Drug Resistance, Neoplasm genetics, GTP Phosphohydrolases genetics, HIV Protease Inhibitors pharmacology, Humans, Membrane Proteins genetics, Mitogen-Activated Protein Kinases metabolism, Nelfinavir pharmacology, PAX3 Transcription Factor, Paired Box Transcription Factors genetics, Proto-Oncogene Proteins B-raf genetics, Up-Regulation drug effects, Up-Regulation genetics, Drug Tolerance genetics, Melanoma drug therapy, Melanoma genetics, Mutation drug effects, Mutation genetics, Protein Kinase Inhibitors pharmacology
- Abstract
Once melanomas have progressed with acquired resistance to mitogen-activated protein kinase (MAPK)-targeted therapy, mutational heterogeneity presents a major challenge. We therefore examined the therapy phase before acquired resistance had developed and discovered the melanoma survival oncogene MITF as a driver of an early non-mutational and reversible drug-tolerance state, which is induced by PAX3-mediated upregulation of MITF. A drug-repositioning screen identified the HIV1-protease inhibitor nelfinavir as potent suppressor of PAX3 and MITF expression. Nelfinavir profoundly sensitizes BRAF and NRAS mutant melanoma cells to MAPK-pathway inhibitors. Moreover, nelfinavir is effective in BRAF and NRAS mutant melanoma cells isolated from patients progressed on MAPK inhibitor (MAPKi) therapy and in BRAF/NRAS/PTEN mutant tumors. We demonstrate that inhibiting a driver of MAPKi-induced drug tolerance could improve current approaches of targeted melanoma therapy., (Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2016
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