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Title: Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis
Authors: Koh K.X.
Tan G.H.
Low S.H.H. 
Omar M.F.M. 
Han M.J.
Iacopetta B.
Soo R. 
Beloueche-Babari M.
Bhattacharya B. 
Soong R. 
Keywords: 2 (2 amino 3 methoxyphenyl)chromone
5 [2 (2,6 dimethylmorpholino) 4 morpholinopyrido[2,3 d]pyrimidin 7 yl] 2 methoxybenzenemethanol
epidermal growth factor receptor
glucose transporter 1
lactic acid
mammalian target of rapamycin
mammalian target of rapamycin inhibitor
mitochondrial DNA
phosphatidylinositol 3 kinase
phosphatidylinositol 3 kinase inhibitor
phosphatidylinositol 3,4,5 trisphosphate 3 phosphatase
protein kinase B
reactive oxygen metabolite
S6 kinase
acquired drug resistance
cell clone
cell metabolism
cell migration
controlled study
DNA sequence
drug resistance
enzyme inhibition
enzyme phosphorylation
G1 phase cell cycle checkpoint
human cell
mitochondrial DNA depletion
NCI-H1975 cell line
oxygen consumption
protein expression
Issue Date: 2017
Publisher: Impact Journals LLC
Citation: Koh K.X., Tan G.H., Low S.H.H., Omar M.F.M., Han M.J., Iacopetta B., Soo R., Beloueche-Babari M., Bhattacharya B., Soong R. (2017). Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis. Oncotarget 8 (66) : 110133-110144. ScholarBank@NUS Repository.
Abstract: Acquired resistance (AQR) to drug treatment occurs frequently in cancer patients and remains an impediment to successful therapy. The aim of this study was to gain insight into how AQR arises following the application of PI3K/mTOR inhibitors. H1975 lung cancer cells with EGFR T790M mutations that confer resistance to EGFR inhibitors underwent prolonged treatment with the PI3K/mTOR inhibitor, BEZ235. Monoclonal cells with stable and increased resistance to BEZ235 were obtained after 8 months treatment. These AQR clones showed class-specific resistance to PI3K/mTOR inhibitors, reduced G1 cell cycle arrest and impedance of migration following PI3K/mTOR inhibition, reduced PTEN expression and increased Akt and S6RP phosphorylation. Transcriptome analysis revealed the AQR clones had increased expression of the metabolite transporters SLC16A9 and SLC16A7, suggestive of altered cell metabolism. Subsequent experiments revealed that AQR clones possess features consistent with elevated glycolysis, including increased levels of glucose, lactate, glutamine, glucose dependence, GLUT1 expression, and rates of post-glucose extracellular acidification, and decreased levels of reactive oxygen species and rates of oxygen consumption. Combination treatment of BEZ235 with the glycolysis inhibitor 3-bromopyruvate was synergistic in AQR clones, but only additive in parental cells. DNA sequencing revealed the presence of a mitochondrial DNA (mtDNA) MT-C01 variant in AQR but not parental cells. Depletion of mitochondrial DNA in parental cells induced resistance to BEZ235 and other PI3K/mTOR inhibitors, and was accompanied by increased glycolysis. The results of this study provide the first evidence that a metabolic switch associated with mtDNA mutation can be an underlying mechanism for AQR. © 2017 Koh et al.
Source Title: Oncotarget
ISSN: 1949-2553
DOI: 10.18632/oncotarget.22655
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