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

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Title: An adaptive signaling network in melanoma inflammatory niches confers tolerance to MAPK signaling inhibition
Author(s): Young, HL
Rowling, EJ
Bugatti, M
Giurisato, E
Luheshi, N
Arozarena, I
Acosta, JC
Kamarashev, J
Frederick, DT
Cooper, ZA
Reuben, A
Gil, J
Flaherty, KT
Wargo, JA
Vermi, W
Smith, MP
Wellbrock, C
Hurlstone, A
Item Type: Journal Article
Abstract: 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
Publication Date: 27-Apr-2017
Date of Acceptance: 10-Mar-2017
URI: http://hdl.handle.net/10044/1/45574
DOI: https://dx.doi.org/10.1084/jem.20160855
ISSN: 1540-9538
Publisher: Rockefeller University Press
Start Page: 1691
End Page: 1710
Journal / Book Title: Journal of Experimental Medicine
Volume: 214
Issue: 6
Copyright Statement: © 2017 Young et al. This article is available under a Creative Commons License (Attribution 4.0 International, as described at https ://creativecommons .org /licenses /by /4 .0 /)
Keywords: Animals
Cell Line, Tumor
Cell Proliferation
Chemokine CXCL1
Fibroblasts
Humans
Inflammation
Interleukin-1
Interleukin-1beta
Interleukin-8
Ligands
MAP Kinase Signaling System
Macrophages
Melanoma
Mice, Knockout
Mitogen-Activated Protein Kinase Kinases
NF-kappa B
Protein Kinase Inhibitors
Proto-Oncogene Proteins B-raf
Proto-Oncogene Proteins c-bcl-2
Receptors, Interleukin-1
Receptors, Interleukin-8B
Skin Neoplasms
Stromal Cells
Cell Line, Tumor
Fibroblasts
Macrophages
Stromal Cells
Animals
Mice, Knockout
Humans
Melanoma
Skin Neoplasms
Inflammation
Proto-Oncogene Proteins B-raf
Mitogen-Activated Protein Kinase Kinases
NF-kappa B
Receptors, Interleukin-8B
Receptors, Interleukin-1
Proto-Oncogene Proteins c-bcl-2
Interleukin-8
Interleukin-1
Protein Kinase Inhibitors
Ligands
Cell Proliferation
MAP Kinase Signaling System
Interleukin-1beta
Chemokine CXCL1
11 Medical And Health Sciences
Immunology
Publication Status: Published
Appears in Collections:Clinical Sciences
Molecular Sciences
Faculty of Medicine



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