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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Podrobná bibliografie
Vydáno v:	Cancer cell Ročník 29; číslo 3; s. 270
Hlavní autoři:	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
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	United States 14.03.2016
Témata:	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
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Popis
Shrnutí:	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.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23
ISSN:	1878-3686 1878-3686
DOI:	10.1016/j.ccell.2016.02.003