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Cancer Cell. 2016 Mar 14;29(3):270-284. doi: 10.1016/j.ccell.2016.02.003.

Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy.

Author information

1
Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK.
2
Molecular Oncology Group, CRUK Manchester Institute for Cancer Research, Manchester Cancer Research Centre, Wilmslow Road, Manchester, M20 4BX, UK.
3
Department of Dermatology, UniversitätsSpital Zürich, University of Zürich, Gloriastrasse 31, 8091 Zurich, Switzerland.
4
Department of Medicine, Massachusetts General Hospital Cancer Center, 55 Fruit Street, Boston, MA 02114-2696, USA.
5
Divison of Surgical Oncology, University of Texas MD Anderson Cancer Center, 1400 Pressler Street, Houston, TX 77030, USA.
6
Manchester Cancer Research Centre, Wellcome Trust Centre for Cell-Matrix Research, The University of Manchester, Michael Smith Building, Oxford Road, Manchester, M13 9PT, UK. Electronic address: claudia.wellbrock@manchester.ac.uk.

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.

PMID:
26977879
PMCID:
PMC4796027
DOI:
10.1016/j.ccell.2016.02.003
[Indexed for MEDLINE]
Free PMC Article

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