PUBLICATION
Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
- Authors
- Smith, M.P., Rowling, E.J., Miskolczi, Z., Ferguson, J., Spoerri, L., Haass, N.K., Sloss, O., McEntegart, S., Arozarena, I., von Kriegsheim, A., Rodriguez, J., Brunton, H., Kmarashev, J., Levesque, M.P., Dummer, R., Frederick, D.T., Andrews, M.C., Cooper, Z.A., Flaherty, K.T., Wargo, J.A., Wellbrock, C.
- ID
- ZDB-PUB-180406-11
- Date
- 2017
- Source
- EMBO Molecular Medicine 9: 1011-1029 (Journal)
- Registered Authors
- Keywords
- AXL, BRAF, MITF, endothelin, melanoma
- MeSH Terms
-
- Animals
- Antineoplastic Agents/therapeutic use*
- Cell Line, Tumor
- Disease Models, Animal
- Endothelin Receptor Antagonists/administration & dosage*
- Heterografts
- Humans
- Melanoma/drug therapy*
- Melanoma/pathology*
- Mice, Nude
- Neoplasm Transplantation
- Proto-Oncogene Proteins B-raf/antagonists & inhibitors*
- Sulfonamides/administration & dosage*
- Treatment Outcome
- Zebrafish
- PubMed
- 28606996 Full text @ EMBO Mol. Med.
Citation
Smith, M.P., Rowling, E.J., Miskolczi, Z., Ferguson, J., Spoerri, L., Haass, N.K., Sloss, O., McEntegart, S., Arozarena, I., von Kriegsheim, A., Rodriguez, J., Brunton, H., Kmarashev, J., Levesque, M.P., Dummer, R., Frederick, D.T., Andrews, M.C., Cooper, Z.A., Flaherty, K.T., Wargo, J.A., Wellbrock, C. (2017) Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure. EMBO Molecular Medicine. 9:1011-1029.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping