A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor Resistance in Melanoma.

Abstract

The purpose of this study is to determine if inhibition of mitochondrial oxidative phosphorylation (OxPhos) is an effective strategy against MAPK pathway inhibitor (MAPKi)-resistant BRAF-mutant melanomas.<b>Experimental Design:</b> The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated <i>in vitro</i> and <i>in vivo</i>. Mechanistic studies and predictors of response were evaluated using molecularly and metabolically stratified melanoma cell lines. ¹³C-labeling and targeted metabolomics were used to evaluate the effect of OPi on cellular energy utilization. OxPhos inhibition <i>in vivo</i> was evaluated noninvasively by [¹⁸F]-fluoroazomycin arabinoside (FAZA) PET imaging. OPi potently inhibited OxPhos and the <i>in vivo</i> growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. <i>In vivo</i> tumor regression with single-agent OPi treatment correlated with inhibition of both MAPK and mTOR complex I activity. Unexpectedly, antitumor activity was not improved by combined treatment with MAPKi <i>in vitro</i> or <i>in vivo</i>. Signaling and growth-inhibitory effects were mediated by LKB1-AMPK axis, and proportional to AMPK activation. OPi increased glucose incorporation into glycolysis, inhibited glucose and glutamine incorporation into the mitochondrial tricarboxylic acid cycle, and decreased cellular nucleotide and amino acid pools. Early changes in [¹⁸F]-FAZA PET uptake <i>in vivo</i>, and the degree of mTORC1 pathway inhibition <i>in vitro</i>, correlated with efficacy. Targeting OxPhos with OPi has significant antitumor activity in MAPKi-resistant, BRAF-mutant melanomas, and merits further clinical investigation as a potential new strategy to overcome intrinsic and acquired resistance to MAPKi in patients.