Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure

Area of Science:

• Oncology
• Molecular Biology
• Dermatology

Background:

• Melanoma treatment response to BRAF inhibitors is often limited by phenotype heterogeneity.
• MITF-high melanomas respond well initially but contain de novo resistant AXL-high subpopulations.
• AXL-high populations are associated with dedifferentiation, invasiveness, and melanoma progression, making their avoidance desirable.

Purpose of the Study:

• To investigate the mechanisms driving phenotype heterogeneity during BRAF inhibitor therapy in melanoma.
• To identify key regulators of melanoma cell subpopulations with differing drug sensitivities.
• To explore therapeutic strategies targeting phenotype heterogeneity to improve BRAF inhibitor efficacy.

Main Methods:

• Analysis of melanoma phenotype heterogeneity in patients undergoing BRAF inhibitor therapy.
• Investigation of the role of endothelin 1 (EDN1) in mediating drug resistance and phenotype switching.
• Assessment of endothelin receptor antagonists in combination with BRAF inhibitors in preclinical models.

Main Results:

• MITF-induced endothelin 1 (EDN1) expression supports phenotype heterogeneity during BRAF inhibitor treatment.
• EDN1 confers drug resistance via paracrine ERK re-activation and supports both MITF-high and AXL-high populations.
• EDN1 acts as a master regulator of phenotype heterogeneity, supporting both sensitive and resistant melanoma subpopulations.

Conclusions:

• Targeting EDN1 signaling, a key regulator of melanoma phenotype heterogeneity, offers a promising strategy to overcome resistance to BRAF inhibitors.
• Endothelin receptor antagonists can suppress AXL-high cells and sensitize melanomas to BRAF inhibition, potentially preventing AXL-high relapse.
• Combined inhibition of EDN1 signaling and BRAF may improve treatment outcomes and prevent the emergence of aggressive melanoma phenotypes.