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.
Highlights
The manifestation of acquired resistance (AQR) to drug treatment following initial response remains a major obstacle in cancer treatment [1, 2]
The results of this study provide the first evidence that a metabolic switch associated with mitochondrial DNA (mtDNA) mutation can be an underlying mechanism for Acquired resistance (AQR)
This study was aimed at bringing further insight into general mechanisms of AQR in the context of the application of phosphoinositide 3-kinase (PI3K)/mammalian target of rapamycin (mTOR) inhibitors to EGFR inhibitorrefractory lung cancer
Summary
The manifestation of acquired resistance (AQR) to drug treatment following initial response remains a major obstacle in cancer treatment [1, 2]. Recent evidence has shown that acquisition of DNA mutations in tumors can be a common mechanism for AQR, especially to molecular-targeted therapies [3]. A prominent example is the emergence of EGFR T790M “gatekeeper” mutations in tumors at the time of disease recurrence and following initial response to EGFR tyrosine kinase inhibitors in nonsmall cell lung cancer (NSCLC) patients. Other examples www.impactjournals.com/oncotarget Drug Class H1975DM H1975C5 H1975C6 BEZ235. PI3K/mTOR inhibitor 0.32 ± 0.13 2.29 ± 0.44* 1.94 ± 0.96*
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