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

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 MIT...

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Bibliographic Details
Published in:Cancer cell Vol. 29; no. 3; p. 270
Main Authors: Smith, Michael P, Brunton, Holly, Rowling, Emily J, Ferguson, Jennifer, Arozarena, Imanol, Miskolczi, Zsofia, Lee, Jessica L, Girotti, Maria R, Marais, Richard, Levesque, Mitchell P, Dummer, Reinhard, Frederick, Dennie T, Flaherty, Keith T, Cooper, Zachary A, Wargo, Jennifer A, Wellbrock, Claudia
Format: Journal Article
Language:English
Published: United States 14.03.2016
Subjects:
Cell Line, Tumor
Drug Resistance, Neoplasm - drug effects
Drug Resistance, Neoplasm - genetics
Drug Tolerance - genetics
GTP Phosphohydrolases - genetics
HIV Protease Inhibitors - pharmacology
Humans
Melanoma - drug therapy
Melanoma - genetics
Membrane Proteins - genetics
Mitogen-Activated Protein Kinases - metabolism
Mutation - drug effects
Mutation - genetics
Nelfinavir - pharmacology
Paired Box Transcription Factors - genetics
PAX3 Transcription Factor
Protein Kinase Inhibitors - pharmacology
Proto-Oncogene Proteins B-raf - genetics
Up-Regulation - drug effects
Up-Regulation - genetics
ISSN:1878-3686, 1878-3686
Online Access:Get more information
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Summary: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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ISSN:1878-3686
1878-3686
DOI:10.1016/j.ccell.2016.02.003