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

ABSTRACT:

Purpose

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.

Results

OPi potently inhibited

SUBMITTER: Vashisht Gopal YN 

PROVIDER: S-EPMC6825560 | biostudies-literature | 2019 Nov

REPOSITORIES: biostudies-literature