Metabolic Imaging Biomarkers of Response to Signaling Inhibition Therapy in Melanoma

Abstract

Dabrafenib therapy for metastatic melanoma focuses on blocking growth-promoting signals produced by a hyperactive BRAF protein. We report the metabolic differences of four human melanoma cell lines with diverse responses to dabrafenib therapy (30 mg/kg; oral): WM3918 < WM9838BR < WM983B < DB-1. Our goal was to determine if metabolic changes produced by the altered signaling pathway due to BRAF mutations differ in the melanoma models and whether these differences correlate with response to treatment. We assessed metabolic changes in isolated cells using high-resolution proton magnetic resonance spectroscopy (1H MRS) and supplementary biochemical assays. We also noninvasively studied mouse xenografts using proton and phosphorus (1H/31P) MRS. We found consistent changes in lactate and alanine, either in isolated cells or mouse xenografts, correlating with their relative dabrafenib responsiveness. In xenografts, we also observed that a more significant response to dabrafenib correlated with higher bioenergetics (i.e., increased βNTP/Pi). Notably, our noninvasive assessment of the metabolic status of the human melanoma xenografts by 1H/31P MRS demonstrated early metabolite changes preceding therapy response (i.e., tumor shrinkage). Therefore, this noninvasive methodology could be translated to assess in vivo predictive metabolic biomarkers of response in melanoma patients under dabrafenib and probably other signaling inhibition therapies.