Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure Academic Article uri icon

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.

authors

  • 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

publication date

  • 2017