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J Exp Med. 2017 Jun 5;214(6):1691-1710. doi: 10.1084/jem.20160855. Epub 2017 Apr 27.

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

Author information

1
Manchester Cancer Research Centre, Faculty of Biology, Medicine, and Health, School of Medical Sciences, Division of Molecular and Clinical Cancer Studies, The University of Manchester, Manchester M13 9PT, England, UK.
2
Department of Molecular and Translational Medicine, Section of Pathology, University of Brescia, 25123 Brescia, Italy.
3
Department of Molecular and Developmental Medicine, University of Siena, 53100 Siena, Italy.
4
Division of Oncology, MedImmune Ltd, Cambridge CB21 6GH, England, UK.
5
Edinburgh Cancer Research Centre, Medical Research Council Institute of Genetics and Molecular Medicine, Western General Hospital, Edinburgh EH4 2XR, Scotland, UK.
6
Department of Dermatology, University Hospital Zürich, 8091 Zürich, Switzerland.
7
Department of Medicine, Massachusetts General Hospital Cancer Center, Boston, MA 02114.
8
Division of Surgical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030.
9
Medical Research Council London Institute of Medical Sciences, London W12 0NN, England, UK.
10
Institute of Clinical Sciences, Faculty of Medicine, Imperial College London, London W12 0NN, England, UK.
11
Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110.
12
Manchester Cancer Research Centre, Faculty of Biology, Medicine, and Health, School of Medical Sciences, Division of Molecular and Clinical Cancer Studies, The University of Manchester, Manchester M13 9PT, England, UK adam.hurlstone@manchester.ac.uk Claudia.Wellbrock@manchester.ac.uk.

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.

PMID:
28450382
PMCID:
PMC5460994
DOI:
10.1084/jem.20160855
[Indexed for MEDLINE]
Free PMC Article

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