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An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition

Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug toleran...

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Autores principales: Young, Helen L., Rowling, Emily J., Bugatti, Mattia, Giurisato, Emanuele, Luheshi, Nadia, Arozarena, Imanol, Acosta, Juan-Carlos, Kamarashev, Jivko, Frederick, Dennie T., Cooper, Zachary A., Reuben, Alexandre, Gil, Jesus, Flaherty, Keith T., Wargo, Jennifer A., Vermi, William, Smith, Michael P., Wellbrock, Claudia, Hurlstone, Adam
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Rockefeller University Press 2017
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460994/
https://www.ncbi.nlm.nih.gov/pubmed/28450382
http://dx.doi.org/10.1084/jem.20160855
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author Young, Helen L.
Rowling, Emily J.
Bugatti, Mattia
Giurisato, Emanuele
Luheshi, Nadia
Arozarena, Imanol
Acosta, Juan-Carlos
Kamarashev, Jivko
Frederick, Dennie T.
Cooper, Zachary A.
Reuben, Alexandre
Gil, Jesus
Flaherty, Keith T.
Wargo, Jennifer A.
Vermi, William
Smith, Michael P.
Wellbrock, Claudia
Hurlstone, Adam
author_facet Young, Helen L.
Rowling, Emily J.
Bugatti, Mattia
Giurisato, Emanuele
Luheshi, Nadia
Arozarena, Imanol
Acosta, Juan-Carlos
Kamarashev, Jivko
Frederick, Dennie T.
Cooper, Zachary A.
Reuben, Alexandre
Gil, Jesus
Flaherty, Keith T.
Wargo, Jennifer A.
Vermi, William
Smith, Michael P.
Wellbrock, Claudia
Hurlstone, Adam
author_sort Young, Helen L.
collection PubMed
description Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment.
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spelling pubmed-54609942017-06-07 An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition Young, Helen L. Rowling, Emily J. Bugatti, Mattia Giurisato, Emanuele Luheshi, Nadia Arozarena, Imanol Acosta, Juan-Carlos Kamarashev, Jivko Frederick, Dennie T. Cooper, Zachary A. Reuben, Alexandre Gil, Jesus Flaherty, Keith T. Wargo, Jennifer A. Vermi, William Smith, Michael P. Wellbrock, Claudia Hurlstone, Adam J Exp Med Research Articles Mitogen-activated protein kinase (MAPK) pathway antagonists induce profound clinical responses in advanced cutaneous melanoma, but complete remissions are frustrated by the development of acquired resistance. Before resistance emerges, adaptive responses establish a mutation-independent drug tolerance. Antagonizing these adaptive responses could improve drug effects, thereby thwarting the emergence of acquired resistance. In this study, we reveal that inflammatory niches consisting of tumor-associated macrophages and fibroblasts contribute to treatment tolerance through a cytokine-signaling network that involves macrophage-derived IL-1β and fibroblast-derived CXCR2 ligands. Fibroblasts require IL-1β to produce CXCR2 ligands, and loss of host IL-1R signaling in vivo reduces melanoma growth. In tumors from patients on treatment, signaling from inflammatory niches is amplified in the presence of MAPK inhibitors. Signaling from inflammatory niches counteracts combined BRAF/MEK (MAPK/extracellular signal–regulated kinase kinase) inhibitor treatment, and consequently, inhibiting IL-1R or CXCR2 signaling in vivo enhanced the efficacy of MAPK inhibitors. We conclude that melanoma inflammatory niches adapt to and confer drug tolerance toward BRAF and MEK inhibitors early during treatment. The Rockefeller University Press 2017-06-05 /pmc/articles/PMC5460994/ /pubmed/28450382 http://dx.doi.org/10.1084/jem.20160855 Text en © 2017 Young et al. https://creativecommons.org/licenses/by/4.0/This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
spellingShingle Research Articles
Young, Helen L.
Rowling, Emily J.
Bugatti, Mattia
Giurisato, Emanuele
Luheshi, Nadia
Arozarena, Imanol
Acosta, Juan-Carlos
Kamarashev, Jivko
Frederick, Dennie T.
Cooper, Zachary A.
Reuben, Alexandre
Gil, Jesus
Flaherty, Keith T.
Wargo, Jennifer A.
Vermi, William
Smith, Michael P.
Wellbrock, Claudia
Hurlstone, Adam
An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title_full An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title_fullStr An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title_full_unstemmed An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title_short An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
title_sort adaptive signaling network in melanoma inflammatory niches confers tolerance to mapk signaling inhibition
topic Research Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5460994/
https://www.ncbi.nlm.nih.gov/pubmed/28450382
http://dx.doi.org/10.1084/jem.20160855
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