Combined HP 13C Pyruvate and 13C-Glucose Fluxomic as a Potential Marker of Response to Targeted Therapies in YUMM1.7 Melanoma Xenografts

A vast majority of BRAF V600E mutated melanoma patients will develop resistance to combined BRAF/MEK inhibition after initial clinical response. Resistance to targeted therapy is described to be accompanied by specific metabolic changes in melanoma. The aim of this work was to evaluate metabolic imaging using C-13-MRS (Magnetic Resonance Spectroscopy) as a marker of response to BRAF/MEK inhibition in a syngeneic melanoma model. Tumor growth was significantly delayed in mice bearing YUMM1 .7 melanoma xenografts treated with the BRAF inhibitor vemurafenib, and/or with the MEK inhibitor trametinib, in comparison with the control group. C-13-MRS was performed in vivo after injection of hyperpolarized (HP) C-13-pyruvate, at baseline and 24 h after treatment, to evaluate dynamic changes in pyruvate-lactate exchange. Furthermore, ex vivo C-13-MRS steady state metabolic tracing experiments were performed after U-C-13-glucose or 5-C-13-glutamine injection, 24 h after treatment. The HP C-13-lactate-to-pyruvate ratio was not modified in response to BRAF/MEK inhibition, whereas the production of C-13-lactate from C-13-glucose was significantly reduced 24 h after treatment with vemurafenib, trametinib, or with the combined inhibitors. Conversely, C-13-glutamine metabolism was not modified in response to BRAF/MEK inhibition. In conclusion, we identified C-13-glucose fluxomic as a potential marker of response to BRAF/MEK inhibition in YUMM1.7 melanoma xenografts.

Automated summary

This study evaluated the metabolic changes in melanoma in response to BRAF/MEK inhibition and identified C-13-glucose metabolism as a potential marker of treatment response.