2 research outputs found
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 âMITFâhighâ phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance âAXLâhighâ phenotype. > 50% of melanomas progress with enriched âAXLâhighâ populations, and because AXL is linked to deâdifferentiation and invasiveness avoiding an âAXLâhigh relapseâ is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITFâinduced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK reâactivation in a paracrine manner. Most importantly, EDN1 not only supports MITFâhigh populations through the endothelin receptor B (EDNRB), but also AXLâhigh populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXLâhighâexpressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXLâhigh cells
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 âMITFâhighâ phenotype usually respond well to BRAF inhibitor therapy, but these melanomas also contain subpopulations of the de novo resistance âAXLâhighâ phenotype. > 50% of melanomas progress with enriched âAXLâhighâ populations, and because AXL is linked to deâdifferentiation and invasiveness avoiding an âAXLâhigh relapseâ is desirable. We discovered that phenotype heterogeneity is supported during the response phase of BRAF inhibitor therapy due to MITFâinduced expression of endothelin 1 (EDN1). EDN1 expression is enhanced in tumours of patients on treatment and confers drug resistance through ERK reâactivation in a paracrine manner. Most importantly, EDN1 not only supports MITFâhigh populations through the endothelin receptor B (EDNRB), but also AXLâhigh populations through EDNRA, making it a master regulator of phenotype heterogeneity. Endothelin receptor antagonists suppress AXLâhighâexpressing cells and sensitize to BRAF inhibition, suggesting that targeting EDN1 signalling could improve BRAF inhibitor responses without selecting for AXLâhigh cells