Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy

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  • dc.contributor.author Redondo Muñoz, Marta
  • dc.contributor.author Heyn, Holger
  • dc.contributor.author Arozarena, Imanol
  • dc.date.accessioned 2023-11-03T07:36:43Z
  • dc.date.available 2023-11-03T07:36:43Z
  • dc.date.issued 2023
  • dc.description.abstract Resistance of melanoma to targeted therapy and immunotherapy is linked to metabolic rewiring. Here, we show that increased fatty acid oxidation (FAO) during prolonged BRAF inhibitor (BRAFi) treatment contributes to acquired therapy resistance in mice. Targeting FAO using the US Food and Drug Administration-approved and European Medicines Agency-approved anti-anginal drug ranolazine (RANO) delays tumour recurrence with acquired BRAFi resistance. Single-cell RNA-sequencing analysis reveals that RANO diminishes the abundance of the therapy-resistant NGFRhi neural crest stem cell subpopulation. Moreover, by rewiring the methionine salvage pathway, RANO enhances melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of RANO with anti-PD-L1 antibodies strongly improves survival by increasing antitumour immune responses. Altogether, we show that RANO increases the efficacy of targeted melanoma therapy through its effects on FAO and the methionine salvage pathway. Importantly, our study suggests that RANO could sensitize BRAFi-resistant tumours to immunotherapy. Since RANO has very mild side-effects, it might constitute a therapeutic option to improve the two main strategies currently used to treat metastatic melanoma.
  • dc.description.sponsorship I.A., P.A., D.E. and A.M. acknowledge funding from the Ministry of Economy and Competitiveness (Institute of Health Carlos III; refs. PI19/00645 to I.A., PI16-01911 to I.A., CPII20/00011 to I.A., CD21/00137 to P.A., PI20/00010 to D.E., PI20/00419 to D.E, PI19/01355 to A.M.). I.A. is also funded by Departamento de Salud del Gobierno de Navarra, Spain (ref. G°Na 71/17) D.A. acknowledges funding from The Spanish Association against Cancer (AECC; PROYE16001ESCO), Biomedicine Project Grant from the Department of Health of the Government of Navarre-FEDER funds (BMED 050-2019, 51-2021) and Strategic projects from the Department of Industry, Government of Navarre (AGATA, ref. 0011-1411; LINTERNA, ref. 0011–1411; DESCARTHES, 0011-1411-2019-000058). M.R.-M. is funded by a PhD studentship from the Department of Industry of the Government of Navarra, Spain and by the Grupo Español Multidisciplinar de Melanoma. The University of Colorado School of Medicine Metabolomics Core is supported in part by the University of Colorado Cancer Center award from the National Cancer Institute P30CA046934. Research in the S.A.B. laboratory is supported partially by the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation programme (grant agreement no. 787041), the Government of Cataluña (SGR grant), the Government of Spain (MINECO), the La Marató/TV3 Foundation, the Foundation Lilliane Bettencourt, the Spanish Association for Cancer Research (AECC) and the Worldwide Cancer Research Foundation (WCRF).
  • dc.format.mimetype application/pdf
  • dc.identifier.citation Redondo-Muñoz M, Rodriguez-Baena FJ, Aldaz P, Caballé-Mestres A, Moncho-Amor V, Otaegi-Ugartemendia M, et al. Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy. Nat Metab. 2023 Sep;5(9):1544-62. DOI: 10.1038/s42255-023-00861-4
  • dc.identifier.doi http://dx.doi.org/10.1038/s42255-023-00861-4
  • dc.identifier.issn 2522-5812
  • dc.identifier.uri http://hdl.handle.net/10230/58207
  • dc.language.iso eng
  • dc.publisher Nature Research
  • dc.relation.ispartof Nat Metab. 2023 Sep;5(9):1544-62
  • dc.relation.projectID info:eu-repo/grantAgreement/EC/H2020/787041
  • dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/PID2019-106852-RBI00
  • dc.rights © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
  • dc.rights.accessRights info:eu-repo/semantics/openAccess
  • dc.rights.uri http://creativecommons.org/licenses/by/4.0/
  • dc.subject.keyword Cancer therapeutic resistance
  • dc.subject.keyword Melanoma
  • dc.title Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy
  • dc.type info:eu-repo/semantics/article
  • dc.type.version info:eu-repo/semantics/publishedVersion

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