Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis
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King Xin Koh1, Gim Hwa Tan2, Sarah Hong Hui Low1, Mohd Feroz Mohd Omar1, Min Ji Han1, Barry Iacopetta3, Ross Soo1,2, Mounia Beloueche-Babari4, Bhaskar Bhattacharya1 and Richie Soong1,5
1Cancer Science Institute of Singapore, National University of Singapore, Singapore, Singapore
2Department of Haematology Oncology, National University Cancer Institute of Singapore, Singapore, Singapore
3School of Biomedical Sciences, The University of Western Australia, Perth, Australia
4Division of Radiotherapy and Imaging, The Institute of Cancer Research and Royal Marsden NHS Foundation Trust, Sutton, United Kingdom
5Department of Pathology, National University of Singapore, Singapore, Singapore
Richie Soong, email: email@example.com
Bhaskar Bhattacharya, email: firstname.lastname@example.org
Keywords: acquired drug resistance; mitochondrial DNA mutation; glycolysis; cancer metabolism; PI3K inhibitors
Received: May 30, 2017 Accepted: October 27, 2017 Published: November 24, 2017
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.
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