Please use this identifier to cite or link to this item: https://hdl.handle.net/11000/30784

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


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Title:
Metabolic rewiring induced by ranolazine improves melanoma responses to targeted therapy and immunotherapy
Authors:
Redondo-Muñoz, Marta
Rodríguez Baena, Francisco Javier  
Aldaz, Paula  
Caballé-Mestres, Adrià
Moncho-Amor, Verónica
Otaegi-Ugartemendia, Maddalen
Carrasco García, Estefanía  
Olias Arjona, Ana  
Lasheras-Otero, Irene
Santamaria, Eva
Bocanegra, Ana
Chocarro, Luisa  
Grier, Abby  
Dzieciatkowska M, Monika
Bigas, Claudia
Martin, Josefina
Urdiroz-Urricelqui, Uxue
Marzo, Florencio
SANTAMARIA, ENRIQUE  
Kochan, Grazyna  
Escors, David
Larrayoz, Ignacio M  
Heyn, Holger  
D’Alessandro, Angelo
Stephan-Otto Attolini, Camille  
matheu, ander  
Wellbrock, Claudia  
Aznar Benitah, Salvador  
Sanchez-Laorden, Berta  
Arozarena, Imanol
Editor:
Nature Portfolio
Issue Date:
2023-08-10
URI:
https://hdl.handle.net/11000/30784
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.
Type of document:
application/pdf
Access rights:
info:eu-repo/semantics/openAccess
Attribution-NonCommercial-NoDerivatives 4.0 Internacional
DOI:
https://doi.org/10.1038/s42255-023-00861-4
Appears in Collections:
Instituto de Neurociencias



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