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dc.contributor.author
Schäfer, Alexander
dc.contributor.author
Haenig, Benedicte
dc.contributor.author
Erupathil, Julie
dc.contributor.author
Strickner, Panja
dc.contributor.author
Sabato, Daniela
dc.contributor.author
Welford, Richard W. D.
dc.contributor.author
Klaeyle, Lheanna
dc.contributor.author
Simon, Elise
dc.contributor.author
Krepler, Clemens
dc.contributor.author
Brafford, Patricia
dc.contributor.author
Xiao, Min
dc.contributor.author
Herlyn, Meenhard
dc.contributor.author
Gstaiger, Matthias
dc.contributor.author
Lehembre, Francois
dc.contributor.author
Renz, Imke
dc.date.accessioned
2021-03-26T11:49:14Z
dc.date.available
2021-02-11T03:48:42Z
dc.date.available
2021-02-11T15:24:21Z
dc.date.available
2021-03-26T11:49:14Z
dc.date.issued
2021-03-04
dc.identifier.issn
0950-9232
dc.identifier.issn
1476-5594
dc.identifier.other
10.1038/s41388-020-01628-x
en_US
dc.identifier.uri
http://hdl.handle.net/20.500.11850/468952
dc.description.abstract
The clinical benefit of MAPK pathway inhibition in melanoma patients carrying BRAF mutations is temporal. After the initial response to treatment, the majority of tumors will develop resistance and patients will relapse. Here we demonstrate that the endothelin-endothelin receptor B (ETBR) signaling pathway confers resistance to MAPK pathway inhibitors in BRAF mutated melanoma. MAPK blockade, in addition to being anti-proliferative, induces a phenotypic change which is characterized by increased expression of melanocyte-specific genes including ETBR. In the presence of MAPK inhibitors, activation of ETBR by endothelin enables the sustained proliferation of melanoma cells. In mouse models of melanoma, including patient-derived xenograft models, concurrent inhibition of the MAPK pathway and ETBR signaling resulted in a more effective anti-tumor response compared to MAPK pathway inhibition alone. The combination treatment significantly reduced tumor growth and prolonged survival compared to therapies with MAPK pathway inhibitors alone. The phosphoproteomic analysis revealed that ETBR signaling did not induce resistance towards MAPK pathway inhibitors by restoring MAPK activity, but instead via multiple alternative signaling pathways downstream of the small G proteins GNAq/11. Together these data indicate that a combination of MAPK pathway inhibitors with ETBR antagonists could have a synergistically beneficial effect in melanoma patients with hyperactivated MAPK signaling pathways.
en_US
dc.language.iso
en
en_US
dc.publisher
Springer Nature
en_US
dc.title
Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma
en_US
dc.type
Journal Article
dc.date.published
2021-01-26
ethz.journal.title
Oncogene
ethz.journal.volume
40
en_US
ethz.journal.issue
9
en_US
ethz.pages.start
1659
en_US
ethz.pages.end
1673
en_US
ethz.identifier.wos
ethz.identifier.scopus
ethz.publication.place
London
en_US
ethz.publication.status
published
en_US
ethz.date.deposited
2021-02-11T03:48:47Z
ethz.source
WOS
ethz.eth
yes
en_US
ethz.availability
Metadata only
en_US
ethz.rosetta.installDate
2021-03-26T11:49:24Z
ethz.rosetta.lastUpdated
2021-03-26T11:49:24Z
ethz.rosetta.versionExported
true
ethz.COinS
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