Summary of Study ST002712
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
This study contains a large results data set and is not available in the mwTab file. It is only available for download via FTP as data file(s) here.
| Study ID | ST002712 |
| Study Title | Ranolazine induced metabolic rewiring improves melanoma responses to targeted therapy and immunotherapy - metabolomics |
| Study Summary | Metabolomics analysis was performed on A375 melanoma cells resistant to BRAF inhibitor vemurafenib (VR) and cells resistant to VR and treated with fatty acid oxidation inhibitor ranolazine. |
| Institute | University of Colorado Denver |
| Last Name | Haines |
| First Name | Julie |
| Address | 12801 E 17th Ave, Room 1303, Aurora, Colorado, 80045, USA |
| julie.haines@cuanschutz.edu | |
| Phone | 3037243339 |
| Submit Date | 2023-05-09 |
| Raw Data Available | Yes |
| Raw Data File Type(s) | raw(Thermo) |
| Analysis Type Detail | LC-MS |
| Release Date | 2023-06-21 |
| Release Version | 1 |
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Project:
| 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 |
