Targeting Endothelin Receptor Signalling Overcomes Heterogeneity Driven Therapy Failure

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.