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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.

Experimental Design: The antimelanoma activity of IACS-010759 (OPi), a novel OxPhos complex I inhibitor, was evaluated in vitro and in vivo. 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 in vivo was evaluated noninvasively by [¹⁸F]-fluoroazomycin arabinoside (FAZA) PET imaging.

OPi potently inhibited OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated …