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dc.contributor.authorSmith, MP
dc.contributor.authorSanchez-Laorden, B
dc.contributor.authorO Brien, K
dc.contributor.authorBrunton, H
dc.contributor.authorFerguson, J
dc.contributor.authorYoung, H
dc.contributor.authorDhomen, N
dc.contributor.authorFlaherty, KT
dc.contributor.authorFrederick, DT
dc.contributor.authorCooper, ZA
dc.contributor.authorWargo, JA
dc.contributor.authorMarais, R
dc.contributor.authorWellbrock, C
dc.date.accessioned2018-08-03T10:52:49Z
dc.date.issued2014-10-01
dc.identifier10
dc.identifier.citationCANCER DISCOVERY, 2014, 4 pp. 1214 - 1229
dc.identifier.issn2159-8274
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/2255
dc.identifier.eissn2159-8290
dc.identifier.doi10.1158/2159-8290.CD-13-1007
dc.description.abstractRecently, the rationale for combining targeted therapy with immunotherapy has come to light, but our understanding of the immune response during MAPK pathway inhibitor treatment is limited. We discovered that the immune microenvironment can act as a source of resistance to MAPK pathway-targeted therapy, and moreover during treatment this source becomes reinforced. In particular, we identified macrophage-derived TNF alpha as a crucial melanoma growth factor that provides resistance to MAPK pathway inhibitors through the lineage transcription factor MITF (microphthalmia transcription factor). Most strikingly, in BRAF-mutant melanomas of patients and BRAF(V600E) melanoma allografts, MAPK pathway inhibitors increased the number of tumor-associated macrophages, and TNF alpha and MITF expression. Inhibiting TNF alpha signaling with I kappa B kinase inhibitors profoundly enhanced the efficacy of MAPK pathway inhibitors by targeting not only the melanoma cells but also the microenvironment. In summary, we identify the immune microenvironment as a novel source of resistance and reveal a new strategy to improve the efficacy of targeted therapy in melanoma. SIGNIFICANCE: This study identifies the immune microenvironment as a source of resistance to MAPK pathway inhibitors through macrophage-derived TNF alpha, and reveals that in patients on treatment this source becomes reinforced. Inhibiting I kappa B kinase enhances the efficacy of MAPK pathway inhibitors, which identifies this approach as a potential novel strategy to improve targeted therapy in melanoma. (C) 2014 AACR.
dc.format.extent1214 - 1229
dc.languageeng
dc.language.isoeng
dc.publisherAMER ASSOC CANCER RESEARCH
dc.rights.urihttps://www.rioxx.net/licenses/all-rights-reserved
dc.titleThe Immune Microenvironment Confers Resistance to MAPK Pathway Inhibitors through Macrophage-Derived TNF alpha
dc.typeJournal Article
rioxxterms.versionofrecord10.1158/2159-8290.CD-13-1007
rioxxterms.licenseref.urihttps://www.rioxx.net/licenses/all-rights-reserved
rioxxterms.licenseref.startdate2014-10
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCANCER DISCOVERY
pubs.notesaffiliation: Wellbrock, C (Reprint Author), Univ Manchester, Michael Smith Bldg,Oxford Rd, Manchester M13 9PT, Lancs, England. Smith, Michael P.; Brunton, Holly; Ferguson, Jennifer; Young, Helen; Wellbrock, Claudia, Univ Manchester, Fac Life Sci, Wellcome Trust Ctr Cell Matrix Res, Manchester Canc Res Ctr, Manchester M13 9PT, Lancs, England. Sanchez-Laorden, Berta; O’Brien, Kate; Dhomen, Nathalie; Marais, Richard, Inst Canc Res, Chester Beatty Labs, Div Canc Biol, London SW3 6JB, England. Sanchez-Laorden, Berta; Marais, Richard, Univ Manchester, Canc Res UK Manchester Inst, Mol Oncol Grp, Manchester M13 9PT, Lancs, England. Flaherty, Keith T.; Frederick, Dennie T., Massachusetts Gen Hosp, Dept Med, Boston, MA 02114 USA. Cooper, Zachary A.; Wargo, Jennifer A., Univ Texas MD Anderson Canc Ctr, Div Surg Oncol, Houston, TX 77030 USA. keywords-plus: NF-KAPPA-B; TUMOR-NECROSIS-FACTOR; HUMAN METASTATIC MELANOMA; BRAF INHIBITION; RAF INHIBITORS; ANTITUMOR-ACTIVITY; MASTER REGULATOR; T-CELLS; CANCER; MICE research-areas: Oncology web-of-science-categories: Oncology author-email: [email protected] researcherid-numbers: Sanchez-Laorden, Berta/T-2177-2017 orcid-numbers: Sanchez-Laorden, Berta/0000-0002-6499-6332 Cooper, Zachary/0000-0003-1059-0940 funding-acknowledgement: Cancer Research UK [C11591/A16416, C15759/A12328, C107/A10433]; Wellcome Trust Institutional Strategic Support Fund (ISSF) award [097820/Z/11/B]; NCI/NIH [U54CA163125]; Biotechnology and Biological Sciences Research Council [1067985]; Cancer Research UK [19279, 17240, 17098, 16416] funding-text: This work was supported by funding from Cancer Research UK (C11591/A16416, to C. Wellbrock; C15759/A12328 and C107/A10433, to R. Marais), a Wellcome Trust Institutional Strategic Support Fund (ISSF) award (097820/Z/11/B) to the University of Manchester, and an NCI/NIH U54CA163125 grant to J.A. Wargo and K.T. Flaherty. number-of-cited-references: 50 times-cited: 52 usage-count-last-180-days: 1 usage-count-since-2013: 18 journal-iso: Cancer Discov. doc-delivery-number: AW8GP unique-id: ISI:000346499800028 oa: gold_or_bronze da: 2018-08-03
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Closed research teams/Signal Transduction
pubs.volume4
pubs.embargo.termsNot known
icr.researchteamSignal Transduction
dc.contributor.icrauthorMarais, Richard Malcolm


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