Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: 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
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Cell Press 2016
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796027/
https://www.ncbi.nlm.nih.gov/pubmed/26977879
http://dx.doi.org/10.1016/j.ccell.2016.02.003
_version_ 1782421697406697472
author 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
author_facet 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
author_sort Smith, Michael P.
collection PubMed
description 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.
format Online
Article
Text
id pubmed-4796027
institution National Center for Biotechnology Information
language English
publishDate 2016
publisher Cell Press
record_format MEDLINE/PubMed
spelling pubmed-47960272016-03-25 Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy 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 Cancer Cell Article 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. Cell Press 2016-03-14 /pmc/articles/PMC4796027/ /pubmed/26977879 http://dx.doi.org/10.1016/j.ccell.2016.02.003 Text en © 2016 The Authors http://creativecommons.org/licenses/by/4.0/ This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
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
Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title_full Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title_fullStr Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title_full_unstemmed Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title_short Inhibiting Drivers of Non-mutational Drug Tolerance Is a Salvage Strategy for Targeted Melanoma Therapy
title_sort inhibiting drivers of non-mutational drug tolerance is a salvage strategy for targeted melanoma therapy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4796027/
https://www.ncbi.nlm.nih.gov/pubmed/26977879
http://dx.doi.org/10.1016/j.ccell.2016.02.003
work_keys_str_mv AT smithmichaelp inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT bruntonholly inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT rowlingemilyj inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT fergusonjennifer inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT arozarenaimanol inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT miskolczizsofia inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT leejessical inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT girottimariar inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT maraisrichard inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT levesquemitchellp inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT dummerreinhard inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT frederickdenniet inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT flahertykeitht inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT cooperzacharya inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT wargojennifera inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy
AT wellbrockclaudia inhibitingdriversofnonmutationaldrugtoleranceisasalvagestrategyfortargetedmelanomatherapy