Combined HP 13 C Pyruvate and 13 C-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 13 C-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. 13 C-MRS was performed in vivo after injection of hyperpolarized (HP) 13 C-pyruvate, at baseline and 24 h after treatment, to evaluate dynamic changes in pyruvate-lactate exchange. Furthermore, ex vivo 13 C-MRS steady state metabolic tracing experiments were performed after U- 13 C-glucose or 5- 13 C-glutamine injection, 24 h after treatment. The HP 13 C-lactate-to-pyruvate ratio was not modified in response to BRAF/MEK inhibition, whereas the production of 13 C-lactate from 13 C-glucose was significantly reduced 24 h after treatment with vemurafenib, trametinib, or with the combined inhibitors. Conversely, 13 C-glutamine metabolism was not modified in response to BRAF/MEK inhibition. In conclusion, we identified 13 C-glucose fluxomic as a potential marker of response to BRAF/MEK inhibition in YUMM1.7 melanoma xenografts.