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Inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy.
Smith, M Brunton, H Rowling, E Ferguson, J Arozarena, I Miskolczi, Z Lee, J Girotti, Maria Romina Marais, Richard Levesque, M
Smith, M
Brunton, H
Rowling, E
Ferguson, J
Arozarena, I
Miskolczi, Z
Lee, J
Girotti, Maria Romina
Marais, Richard
Levesque, M
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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.
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Date
2016-03-14
Publisher
Collections
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Type
Article
Citation
Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy. 2016, 29 (3):270-84 Cancer Cell