TY - JOUR
T1 - A novel mitochondrial inhibitor blocks MAPK pathway and overcomes MAPK inhibitor resistance in melanoma
AU - Gopal, Y. N.Vashisht
AU - Gammon, Seth
AU - Prasad, Rishika
AU - Knighton, Barbara
AU - Pisaneschi, Federica
AU - Roszik, Jason
AU - Feng, Ningping
AU - Johnson, Sarah
AU - Pramanik, Snigdha
AU - Sudderth, Jessica
AU - Sui, Dawen
AU - Hudgens, Courtney
AU - Fischer, Grant M.
AU - Deng, Wanleng
AU - Reuben, Alexandre
AU - Peng, Weiyi
AU - Wang, Jian
AU - McQuade, Jennifer L.
AU - Tetzlaff, Michael T.
AU - Di Francesco, Maria E.
AU - Marszalek, Joe
AU - Piwnica-Worms, David
AU - DeBerardinis, Ralph J.
AU - Davies, Michael A.
N1 - Funding Information:
Y.N. Vashisht Gopal is supported by Melanoma Research Alliance. M.A. Davies is supported by the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation, philanthropic contributions to the Melanoma Moon Shots Program of the UT MD Anderson Cancer Center, AIM at Melanoma Foundation, NIH/NCI (2T32CA009666-21), and the Cancer Prevention Research Institute of Texas (CPRIT; RP170401). M.A. Davies, R.J. DeBerardinis, and Y.N. Vashisht Gopal are supported by CPRIT IIRA grant (RP160183). S. Gammon and D. Piwnica-Worms were supported by a NIH/NCI Molecular Imaging Center grant (P50 CA094056). G.M. Fischer is supported by the Caroline Ross Fellowship of MDACC, the Schissler Foundation Fellowship of UT-Health/MDACC, and the NIH National Center for Advancing Translational Sciences (TL1TR000369 and UL1TR000371). RPPA and SAIF core facilities at MDACC are supported by NCI #CA16672. RPPA core facility at MDACC is supported by NCI #CA16672. Chunyu Xu and Victoria Thiele provided technical support.
Publisher Copyright:
© 2019 American Association for Cancer Research.
PY - 2019/11/1
Y1 - 2019/11/1
N2 - 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 OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo 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 in vitro or in vivo. 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 in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy. Conclusions: 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.
AB - 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 OxPhos and the in vivo growth of multiple MAPKi-resistant BRAF-mutant melanoma models with high OxPhos at well-tolerated doses. In vivo 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 in vitro or in vivo. 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 in vivo, and the degree of mTORC1 pathway inhibition in vitro, correlated with efficacy. Conclusions: 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.
UR - http://www.scopus.com/inward/record.url?scp=85074379267&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85074379267&partnerID=8YFLogxK
U2 - 10.1158/1078-0432.CCR-19-0836
DO - 10.1158/1078-0432.CCR-19-0836
M3 - Article
C2 - 31439581
AN - SCOPUS:85074379267
SN - 1078-0432
VL - 25
SP - 6429
EP - 6442
JO - Clinical Cancer Research
JF - Clinical Cancer Research
IS - 21
ER -