Acquired resistance to PI3K/mTOR inhibition is associated with mitochondrial DNA mutation and glycolysis

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.

PRDM15 is a key regulator of metabolism critical to sustain B-cell lymphomagenesis

“…A substantial crosstalk exists between mTOR signaling and glycolysis, which often leads to activation of compensatory mechanisms to bypass inhibition of one axis or the other 38 – 40 . Combined inhibition of these axes was suggested to provide efficient therapeutic strategy in several cancer types.…”

“…PRDM15 regulates central carbon metabolism in B-cell lymphomas. Recent studies have shown that mTOR inhibition is not effective as monotherapy; several cancer types bypass this inhibition by upregulating glycolysis, while suppression of glycolysis is bypassed by hyperactivation of mTOR and subsequent metabolic reprogramming [38][39][40] .…”

Targeting PI3K in cancer: mechanisms and advances in clinical trials

“…Not surprisingly, more and more researches have suggested that deviant ncRNA expression is powerfully concerned about tumor drug resistance [200][201][202][203][204][205][206][207][208]. Recent studies have indicated potential mechanism of acquired resistance to dual PI3K/mTOR inhibitors, including elevated glycolysis accompanied with depletion of mitochondrial DNA, and upregulated DNA methyltransferases which Reduce PTEN and PPP2R2B expression [209,210]. Novel roles of the tumor microenvironment have introduced in regulating drug resistance, and macrophages in microenvironment have been proposed as factors contributing to the resistances of PI3K inhibitors through the activation of NF-κB signaling [211].…”

Functional and genomic characterization of patient‐derived xenograft model to study the adaptation to mTORC1 inhibitor in clear cell renal cell carcinoma

“…Moreover, other report showed that using WES for pre‐treatment and post‐treatment tumor samples in six RCC cases, genetic alterations involving mTOR pathway were not newly acquired through mTOR inhibitor treatment 40 . In human lung cancer cell lines, acquired resistance to PI3K/mTOR inhibition was documented after increased glycolysis associated with mitochondrial DNA mutations 41 . Additionally, negative feedback loops, alternative pathway activation, and tumor heterogeneity were found to be related to mTOR resistance 11 .…”

“…40 In human lung cancer cell lines, acquired resistance to PI3K/ mTOR inhibition was documented after increased glycolysis associated with mitochondrial DNA mutations. 41 Additionally, negative feedback loops, alternative pathway activation, and tumor heterogeneity were found to be related to mTOR resistance. 11 Indeed, other study suggested that using ccRCC cell lines from PDX, mTOR inhibition-induced alternative MEK activation.…”