Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Smith, Michael P., Rowling, Emily J., Miskolczi, Zsofia, Ferguson, Jennifer, Spoerri, Loredana, Haass, Nikolas K., Sloss, Olivia, Mcentegart, Sophie, Arozarena, Imanol, von Kriegsheim, Alex, Rodriguez, Javier, Brunton, Holly, Kmarashev, Jivko, Levesque, Mitchell P., Dummer, Reinhard, Frederick, Dennie T., Andrews, Miles C., Cooper, Zachary A., Flaherty, Keith T., Wargo, Jennifer A. and Wellbrock, Claudia (2017) Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure. EMBO Molecular Medicine, 9 8: 1011-1029. doi:10.15252/emmm.201607156


Author Smith, Michael P.
Rowling, Emily J.
Miskolczi, Zsofia
Ferguson, Jennifer
Spoerri, Loredana
Haass, Nikolas K.
Sloss, Olivia
Mcentegart, Sophie
Arozarena, Imanol
von Kriegsheim, Alex
Rodriguez, Javier
Brunton, Holly
Kmarashev, Jivko
Levesque, Mitchell P.
Dummer, Reinhard
Frederick, Dennie T.
Andrews, Miles C.
Cooper, Zachary A.
Flaherty, Keith T.
Wargo, Jennifer A.
Wellbrock, Claudia
Title Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
Journal name EMBO Molecular Medicine   Check publisher's open access policy
ISSN 1757-4684
Publication date 2017-06-12
Sub-type Article (original research)
DOI 10.15252/emmm.201607156
Open Access Status DOI
Volume 9
Issue 8
Start page 1011
End page 1029
Total pages 19
Place of publication Weinheim, Germany
Publisher Wiley - VCH
Language eng
Subject 1313 Molecular Medicine
Abstract Approaches to prolong responses to BRAF targeting drugs in melanoma patients are challenged by phenotype heterogeneity. Melanomas of a “MITF‐high” phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance “AXL‐high” phenotype. > 50% of melanomas progress with enriched “AXL‐high” populations, and because AXL is linked to de‐differentiation and invasiveness avoiding an “AXL‐high relapse” is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITF‐induced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK re‐activation in a paracrine manner. Most importantly, EDN1 not only supports MITF‐high populations through the endothelin receptor B (EDNRB), but also AXL‐high populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXL‐high‐expressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXL‐high cells.
Keyword AXL
BRAF
Endothelin
Melanoma
MITF
Q-Index Code C1
Q-Index Status Provisional Code
Grant ID 12-0235
APP1084893
C11591/A16416
K08CA160692
R116433
RG 13-06
U54CA163125
Institutional Status UQ
Additional Notes Published online 12 June 2017

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
UQ Diamantina Institute Publications
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Created: Tue, 27 Jun 2017, 13:03:22 EST by Nikolas Haass on behalf of Learning and Research Services (UQ Library)