Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Michael P Smith, Emily J Rowling, Zsofia Miskolczi, Jennifer Ferguson, Loredana Spoerri, Nikolas K Haass, Olivia Sloss, Sophie McEntegart, Imanol Arozarena, Alex von Kriegsheim, Javier Rodriguez, Holly Brunton, Jivko Kmarashev, Mitchell P Levesque, Reinhard Dummer, Dennie T Frederick, Miles C Andrews, Zachary A Cooper, Keith T Flaherty, Jennifer A WargoClaudia Wellbrock

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
JournalEMBO Molecular Medicine
Early online date12 Jun 2017
DOIs
Publication statusE-pub ahead of print - 12 Jun 2017

Keywords

  • Journal Article

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