Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure
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” p...
| Main Authors: | , , , , , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2017-06-01
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| Series: | EMBO Molecular Medicine |
| Subjects: | |
| Online Access: | https://doi.org/10.15252/emmm.201607156 |
| _version_ | 1827059770279854080 |
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| author | Michael P Smith Emily J Rowling Zsofia Miskolczi Jennifer Ferguson Loredana Spoerri Nikolas K Haass Olivia Sloss Sophie McEntegart Imanol Arozarena Alex von Kriegsheim Javier Rodriguez Holly Brunton Jivko Kmarashev Mitchell P Levesque Reinhard Dummer Dennie T Frederick Miles C Andrews Zachary A Cooper Keith T Flaherty Jennifer A Wargo Claudia Wellbrock |
| author_facet | Michael P Smith Emily J Rowling Zsofia Miskolczi Jennifer Ferguson Loredana Spoerri Nikolas K Haass Olivia Sloss Sophie McEntegart Imanol Arozarena Alex von Kriegsheim Javier Rodriguez Holly Brunton Jivko Kmarashev Mitchell P Levesque Reinhard Dummer Dennie T Frederick Miles C Andrews Zachary A Cooper Keith T Flaherty Jennifer A Wargo Claudia Wellbrock |
| author_sort | Michael P Smith |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-07T16:44:22Z |
| format | Article |
| id | doaj.art-7cabb6c3861544079d79157438ec0d09 |
| institution | Directory Open Access Journal |
| issn | 1757-4676 1757-4684 |
| language | English |
| last_indexed | 2025-02-18T18:47:46Z |
| publishDate | 2017-06-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj.art-7cabb6c3861544079d79157438ec0d092024-10-20T11:37:22ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842017-06-01981011102910.15252/emmm.201607156Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failureMichael P Smith0Emily J Rowling1Zsofia Miskolczi2Jennifer Ferguson3Loredana Spoerri4Nikolas K Haass5Olivia Sloss6Sophie McEntegart7Imanol Arozarena8Alex von Kriegsheim9Javier Rodriguez10Holly Brunton11Jivko Kmarashev12Mitchell P Levesque13Reinhard Dummer14Dennie T Frederick15Miles C Andrews16Zachary A Cooper17Keith T Flaherty18Jennifer A Wargo19Claudia Wellbrock20Manchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterTranslational Research Institute, The University of Queensland Diamantina Institute, The University of QueenslandTranslational Research Institute, The University of Queensland Diamantina Institute, The University of QueenslandManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterSystems Biology Ireland, School of Medicine, UCDSystems Biology Ireland, School of Medicine, UCDManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterDepartment of Dermatology, Universitätsspital Zürich, University of ZurichDepartment of Dermatology, Universitätsspital Zürich, University of ZurichDepartment of Dermatology, Universitätsspital Zürich, University of ZurichDepartment of Medicine, Massachusetts General Hospital Cancer CenterDivision of Surgical Oncology, University of Texas MD Anderson Cancer CenterDivision of Surgical Oncology, University of Texas MD Anderson Cancer CenterDepartment of Medicine, Massachusetts General Hospital Cancer CenterDivision of Surgical Oncology, University of Texas MD Anderson Cancer CenterManchester Cancer Research Centre, Faculty of Biology, Medicine and Health, The University of ManchesterAbstract 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.https://doi.org/10.15252/emmm.201607156AXLBRAFendothelinmelanomaMITF |
| spellingShingle | Michael P Smith Emily J Rowling Zsofia Miskolczi Jennifer Ferguson Loredana Spoerri Nikolas K Haass Olivia Sloss Sophie McEntegart Imanol Arozarena Alex von Kriegsheim Javier Rodriguez Holly Brunton Jivko Kmarashev Mitchell P Levesque Reinhard Dummer Dennie T Frederick Miles C Andrews Zachary A Cooper Keith T Flaherty Jennifer A Wargo Claudia Wellbrock Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure EMBO Molecular Medicine AXL BRAF endothelin melanoma MITF |
| title | Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| title_full | Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| title_fullStr | Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| title_full_unstemmed | Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| title_short | Targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| title_sort | targeting endothelin receptor signalling overcomes heterogeneity driven therapy failure |
| topic | AXL BRAF endothelin melanoma MITF |
| url | https://doi.org/10.15252/emmm.201607156 |
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