Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

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

Research output: Contribution to journalArticlepeer-review


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 dedifferentiation 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 drugresistance 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
Publication statusPublished - 12 Jun 2017


  • Melanoma
  • Endothelin
  • MITF
  • AXL
  • BRAF

Research Beacons, Institutes and Platforms

  • Manchester Cancer Research Centre


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