PMID- 31439581
OWN - NLM
STAT- MEDLINE
DCOM- 20200908
LR  - 20211204
IS  - 1557-3265 (Electronic)
IS  - 1078-0432 (Print)
IS  - 1078-0432 (Linking)
VI  - 25
IP  - 21
DP  - 2019 Nov 1
TI  - A Novel Mitochondrial Inhibitor Blocks MAPK Pathway and Overcomes MAPK Inhibitor 
      Resistance in Melanoma.
PG  - 6429-6442
LID - 10.1158/1078-0432.CCR-19-0836 [doi]
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. (13)C-labeling and targeted metabolomics were used to evaluate the 
      effect of OPi on cellular energy utilization. OxPhos inhibition in vivo was 
      evaluated noninvasively by [(18)F]-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 [(18)F]-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.
CI  - (c)2019 American Association for Cancer Research.
FAU - Vashisht Gopal, Y N
AU  - Vashisht Gopal YN
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas. vynanda@mdanderson.org.
AD  - Department of Translational Molecular Pathology, University of Texas M.D. 
      Anderson Cancer Center, Houston, Texas.
FAU - Gammon, Seth
AU  - Gammon S
AUID- ORCID: 0000-0001-8647-0975
AD  - Department of Cancer Systems Imaging, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Prasad, Rishika
AU  - Prasad R
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Knighton, Barbara
AU  - Knighton B
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Pisaneschi, Federica
AU  - Pisaneschi F
AUID- ORCID: 0000-0002-1989-4417
AD  - Department of Cancer Systems Imaging, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Roszik, Jason
AU  - Roszik J
AUID- ORCID: 0000-0002-4561-6170
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Feng, Ningping
AU  - Feng N
AUID- ORCID: 0000-0003-1917-9648
AD  - Center for Co-Clinical Trials, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Johnson, Sarah
AU  - Johnson S
AD  - Center for Co-Clinical Trials, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Pramanik, Snigdha
AU  - Pramanik S
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Sudderth, Jessica
AU  - Sudderth J
AD  - Children's Medical Research Institute, University of Texas Southwestern Medical 
      Center, Dallas, Texas.
FAU - Sui, Dawen
AU  - Sui D
AD  - Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Hudgens, Courtney
AU  - Hudgens C
AUID- ORCID: 0000-0001-8312-7485
AD  - Department of Translational Molecular Pathology, University of Texas M.D. 
      Anderson Cancer Center, Houston, Texas.
FAU - Fischer, Grant M
AU  - Fischer GM
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
AD  - Department of Cancer Biology, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Deng, Wanleng
AU  - Deng W
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Reuben, Alexandre
AU  - Reuben A
AUID- ORCID: 0000-0003-4510-0382
AD  - Department of Thoracic H&N Medical Oncology, University of Texas M.D. Anderson 
      Cancer Center, Houston, Texas.
FAU - Peng, Weiyi
AU  - Peng W
AUID- ORCID: 0000-0002-7785-6240
AD  - Department of Biology and Biochemistry, University of Houston, Houston, Texas.
FAU - Wang, Jian
AU  - Wang J
AD  - Department of Biostatistics, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - McQuade, Jennifer L
AU  - McQuade JL
AUID- ORCID: 0000-0002-2393-2172
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Tetzlaff, Michael T
AU  - Tetzlaff MT
AUID- ORCID: 0000-0002-0977-0912
AD  - Department of Translational Molecular Pathology, University of Texas M.D. 
      Anderson Cancer Center, Houston, Texas.
AD  - Department of Pathology, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Di Francesco, Maria E
AU  - Di Francesco ME
AD  - Institute for Applied Cancer Science, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - Marszalek, Joe
AU  - Marszalek J
AD  - Center for Co-Clinical Trials, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
FAU - Piwnica-Worms, David
AU  - Piwnica-Worms D
AD  - Department of Cancer Systems Imaging, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
FAU - DeBerardinis, Ralph J
AU  - DeBerardinis RJ
AD  - Children's Medical Research Institute, University of Texas Southwestern Medical 
      Center, Dallas, Texas.
AD  - Howard Hughes Medical Institute, Chevy Chase, Maryland.
FAU - Davies, Michael A
AU  - Davies MA
AUID- ORCID: 0000-0002-0977-0912
AD  - Department of Melanoma Medical Oncology, University of Texas M.D. Anderson Cancer 
      Center, Houston, Texas.
AD  - Department of Translational Molecular Pathology, University of Texas M.D. 
      Anderson Cancer Center, Houston, Texas.
AD  - Department of Systems Biology, University of Texas M.D. Anderson Cancer Center, 
      Houston, Texas.
LA  - eng
GR  - P50 CA094056/CA/NCI NIH HHS/United States
GR  - P30 CA016672/CA/NCI NIH HHS/United States
GR  - R01 CA231506/CA/NCI NIH HHS/United States
GR  - UL1 TR000371/TR/NCATS NIH HHS/United States
GR  - TL1 TR000369/TR/NCATS NIH HHS/United States
GR  - T32 CA009666/CA/NCI NIH HHS/United States
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190822
PL  - United States
TA  - Clin Cancer Res
JT  - Clinical cancer research : an official journal of the American Association for 
      Cancer Research
JID - 9502500
RN  - 0 (IACS-010759)
RN  - 0 (Oxadiazoles)
RN  - 0 (Piperidines)
RN  - 0 (Protein Kinase Inhibitors)
RN  - EC 2.7.- (Protein Kinases)
RN  - EC 2.7.1.1 (MTOR protein, human)
RN  - EC 2.7.11.1 (BRAF protein, human)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins B-raf)
RN  - EC 2.7.11.1 (TOR Serine-Threonine Kinases)
RN  - EC 2.7.11.3 (AMP-Activated Protein Kinase Kinases)
SB  - IM
MH  - AMP-Activated Protein Kinase Kinases
MH  - Animals
MH  - Cell Line, Tumor
MH  - Drug Resistance, Neoplasm/drug effects
MH  - Gene Expression Regulation, Neoplastic/drug effects
MH  - Heterografts
MH  - Humans
MH  - MAP Kinase Signaling System/*drug effects
MH  - Melanoma/*drug therapy/genetics/pathology
MH  - Mice
MH  - Mitochondria/drug effects
MH  - Oxadiazoles/therapeutic use
MH  - Oxidative Phosphorylation/*drug effects
MH  - Piperidines/therapeutic use
MH  - Positron-Emission Tomography
MH  - Protein Kinase Inhibitors/*pharmacology/therapeutic use
MH  - Protein Kinases/genetics
MH  - Proto-Oncogene Proteins B-raf/genetics
MH  - TOR Serine-Threonine Kinases/genetics
PMC - PMC6825560
MID - NIHMS1537664
COIS- Conflict of Interest Disclosure: Y.N. Vashisht Gopal has a research grant from 
      Calithera Biosciences. M. Tetzlaff is on the advisory board of Myriad Genetics, 
      Seattle Genetics and Novartis. M.A. Davies is a consultant to Nanostring 
      Technologies, and on advisory boards for Novartis, Bristol Myers Squibb, 
      GlaxoSmithKline, Roche-Genentech, Sanofi-Aventis, Vaccinex, and Array Biopharma; 
      and has institutional research grants from Astrazeneca, GlaxoSmithkline, 
      Roche-Genentech, Sanofi-Aventis, Merck, Oncothyreon, and Myriad Genetics. UT M.D. 
      Anderson Cancer Center has a patent on IACS-010759 (OPi).
EDAT- 2019/08/24 06:00
MHDA- 2020/09/09 06:00
PMCR- 2020/05/01
CRDT- 2019/08/24 06:00
PHST- 2019/03/12 00:00 [received]
PHST- 2019/06/25 00:00 [revised]
PHST- 2019/08/09 00:00 [accepted]
PHST- 2019/08/24 06:00 [pubmed]
PHST- 2020/09/09 06:00 [medline]
PHST- 2019/08/24 06:00 [entrez]
PHST- 2020/05/01 00:00 [pmc-release]
AID - 1078-0432.CCR-19-0836 [pii]
AID - 10.1158/1078-0432.CCR-19-0836 [doi]
PST - ppublish
SO  - Clin Cancer Res. 2019 Nov 1;25(21):6429-6442. doi: 10.1158/1078-0432.CCR-19-0836. 
      Epub 2019 Aug 22.