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Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma

Oncogene volume 40, pages 1659–1673 (2021)Cite this article

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Abstract

The clinical benefit of MAPK pathway inhibition in melanoma patients carrying BRAF mutations is temporal. After the initial response to treatment, the majority of tumors will develop resistance and patients will relapse. Here we demonstrate that the endothelin-endothelin receptor B (ETBR) signaling pathway confers resistance to MAPK pathway inhibitors in BRAF mutated melanoma. MAPK blockade, in addition to being anti-proliferative, induces a phenotypic change which is characterized by increased expression of melanocyte-specific genes including ETBR. In the presence of MAPK inhibitors, activation of ETBR by endothelin enables the sustained proliferation of melanoma cells. In mouse models of melanoma, including patient-derived xenograft models, concurrent inhibition of the MAPK pathway and ETBR signaling resulted in a more effective anti-tumor response compared to MAPK pathway inhibition alone. The combination treatment significantly reduced tumor growth and prolonged survival compared to therapies with MAPK pathway inhibitors alone. The phosphoproteomic analysis revealed that ETBR signaling did not induce resistance towards MAPK pathway inhibitors by restoring MAPK activity, but instead via multiple alternative signaling pathways downstream of the small G proteins GNAq/11. Together these data indicate that a combination of MAPK pathway inhibitors with ETBR antagonists could have a synergistically beneficial effect in melanoma patients with hyperactivated MAPK signaling pathways.

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Fig. 1: BRAF inhibition induces a melanocytic phenotype in BRAF mutated melanomas.
Fig. 2: ETBR signaling is a specific resistance mechanism towards MAPK pathway inhibitors.
Fig. 3: Combination treatment of melanoma bearing mice with MAPK pathway inhibitors and an ETBR antagonist inhibits tumor growth and prolongs survival compared to treatment with MAPK pathway inhibitors only.
Fig. 4: Targeting ETBR signaling in BRAF-mutated patient-derived melanomas.
Fig. 5: ET-1 mediated resistance and MAPK signaling.
Fig. 6: Reactivation of MAPK signaling is not the driver of ET-1 mediated resistance to MAPK pathway inhibition.
Fig. 7: ET-1 induced phosphorylation changes upon MAPK inhibition.
Fig. 8: ET-1 mediated MAPK inhibitor resistance is dependent upon GNAq/11 activation.

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Funding

The study was funded by Idorsia Pharmaceuticals Ltd.

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Author notes

  1. Alexander Schäfer

    Present address: Swiss BioQuant AG, 4153, Reinach, Switzerland

  2. Elise Simon

    Present address: Novartis Institutes for BioMedical Research, 4002, Basel, Switzerland

  3. Clemens Krepler

    Present address: Merck, North Wales, PA, 19454, USA

  4. These authors contributed equally: Alexander Schäfer, Benedicte Haenig

Authors and Affiliations

  1. Department of Biology, Institute of Molecular Systems Biology, ETH Zürich, Otto-Stern-Weg 3, 8093, Zürich, Switzerland

    Alexander Schäfer & Matthias Gstaiger

  2. Drug Discovery Biology, Idorsia Pharmaceuticals Ltd., Hegenheimermattweg 91, 4123, Allschwil, Switzerland

    Benedicte Haenig, Julie Erupathil, Panja Strickner, Daniela Sabato, Richard W. D. Welford, Lhéanna Klaeylé, Elise Simon, Francois Lehembre & Imke Renz

  3. Molecular and Cellular Oncogenesis Program and Melanoma Research Center, The Wistar Institute, Philadelphia, PA, 19104, USA

    Clemens Krepler, Patricia Brafford, Min Xiao & Meenhard Herlyn

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IR, BH, JE, PS, DS, RWDW, LK, and FL are full-time employees of Idorsia Pharmaceuticals Ltd. ES was a full-time employee of Idorsia Pharmaceuticals Ltd. at the time of the study. This manuscript has been read and approved by all authors and is not under consideration for publication elsewhere.

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Schäfer, A., Haenig, B., Erupathil, J. et al. Inhibition of endothelin-B receptor signaling synergizes with MAPK pathway inhibitors in BRAF mutated melanoma. Oncogene 40, 1659–1673 (2021). https://doi.org/10.1038/s41388-020-01628-x

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