Summary of project PR001681
This data is available at the NIH Common Fund's National Metabolomics Data Repository (NMDR) website, the Metabolomics Workbench, https://www.metabolomicsworkbench.org, where it has been assigned Project ID PR001681. The data can be accessed directly via it's Project DOI: 10.21228/M8DT5S This work is supported by NIH grant, U2C- DK119886.
See: https://www.metabolomicsworkbench.org/about/howtocite.php
| Project ID: | PR001681 |
| Project DOI: | doi: 10.21228/M8DT5S |
| Project Title: | Ranolazine induced metabolic rewiring improves melanoma responses to targeted therapy and immunotherapy |
| Project Summary: | Metabolic rewiring affects resistance of melanoma to targeted- and immuno-therapy. We have found that increased fatty acid oxidation (FAO) during late stages of BRAF inhibitor (BRAFi) treatment enables the establishment of acquired resistance. Targeting FAO with ranolazine in vivo once acquired BRAFi-resistance emerges delays tumour recurrence. Single cell RNAseq analysis revealed that ranolazine diminishes the transcriptional NGFRhigh neural crest stem cell subpopulation, which is refractory against BRAFi and immunotherapy. Moreover, by rewiring the methionine salvage pathway, ranolazine enhanced melanoma immunogenicity through increased antigen presentation and interferon signalling. Combination of ranolazine with anti-PD-L1 antibodies strongly improved survival in mice, where it increased lymphocyte infiltration and enhanced anti-tumour responses. Altogether, we show that ranolazine increases the efficacy of targeted melanoma therapy through fatty acid and methionine salvage metabolic rewiring. Importantly, our study suggests that ranolazine could sensitize BRAFi-resistant tumours to immunotherapy, by modulating melanoma cell recognition and immune infiltration. Ranolazine is an FDA and EMA-approved anti-anginal drug with very mild side effects, and our preclinical data encourage its use as a therapeutic option to improve the two main therapeutic strategies currently used to treat metastatic melanoma. |
| Institute: | University of Colorado Denver |
| Laboratory: | Lab of Angelo D'Alessandro in collaboration with lab of Imanol Arozarena |
| Last Name: | Haines |
| First Name: | Julie |
| Address: | 12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA |
| Email: | julie.haines@cuanschutz.edu |
| Phone: | 3037243339 |
Summary of all studies in project PR001681
| Study ID | Study Title | Species | Institute | Analysis(* : Contains Untargted data) | Release Date | Version | Samples | Download(* : Contains raw data) |
|---|---|---|---|---|---|---|---|---|
| ST002712 | Ranolazine induced metabolic rewiring improves melanoma responses to targeted therapy and immunotherapy - metabolomics | Homo sapiens | University of Colorado Denver | MS | 2023-06-21 | 1 | 12 | Uploaded data (1.5G)* |
| ST002713 | Ranolazine induced metabolic rewiring improves melanoma responses to targeted therapy and immunotherapy - lipidomics | Homo sapiens | University of Colorado Denver | MS | 2023-06-21 | 1 | 12 | Uploaded data (1.1G)* |
