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

2023; Nature Portfolio; Volume: 5; Issue: 9 Linguagem: Inglês

10.1038/s42255-023-00861-4

2522-5812

Marta Redondo-Muñoz, Francisco Javier Rodríguez‐Baena, Paula Aldaz, Adrià Caballé, Verónica Moncho-Amor, Maddalen Otaegi-Ugartemendia, Estefanía Carrasco‐García, Ana Olías-Arjona, Irene Otero, Eva Santamaría, Ana Bocanegra, Luisa Chocarro, Abby Grier, Monika Dzieciątkowska, Claudia Bigas, Josefina Martin, Uxue Urdiroz-Urricelqui, Florencio Marzo, Enrique Santamaría, Grazyna Kochan, David Escors, Ignacio M. Larráyoz, Holger Heyn, Angelo D’Alessandro, Camille Stephan‐Otto Attolini, Ander Matheu, Claudia Wellbrock, Salvador Aznar Benitah, Berta Sánchez-Laorden, Imanol Arozarena,

Melanoma and MAPK Pathways

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.