Open AccessTargeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
Author(s) -
Smith Michael P,
Rowling Emily J,
Miskolczi Zsofia,
Ferguson Jennifer,
Spoerri Loredana,
Haass Nikolas K,
Sloss Olivia,
McEntegart Sophie,
Arozarena Imanol,
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 year - 2017
Publication title -
embo molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 4.923
H-Index - 107
eISSN - 1757-4684
pISSN - 1757-4676
DOI - 10.15252/emmm.201607156
Subject(s) - phenotype , microphthalmia associated transcription factor , cancer research , biology , melanoma , paracrine signalling , receptor , targeted therapy , endothelin receptor , genetics , transcription factor , cancer , gene
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.