Inhibition of DNA methyltransferase as a novel therapeutic strategy to overcome acquired resistance to dual PI3K/mTOR inhibitors

Abstract

Dual PI3K/mTOR(phosphatidylinositol 3-kinase/mammalian target of rapamycin) inhibitors are being evaluated clinically for the treatment of tumors with a hyperactivated PI3K/mTOR pathway. However, unexpected outcomes were obtained in clinical studies of cancer patients with an aberrant PI3K pathway. In clinical trials, applicable combination regimens are not yet available. In this study, using an integrated analysis of acquired BEZ235-resistant nasopharyngeal carcinoma cells, we demonstrate that DNA methyltransferase is a key modulator and a common node upstream of the AKT/mTOR and PDK1/MYC pathways, which are activated in cancer cells with acquired BEZ235 resistance. DNA methyltransferases were upregulated and induced PTEN and PPP2R2B gene hypermethylation, which downregulated their expression in BEZ235-resistant cancer cells. Reduced PTEN and PPP2R2B expression correlated with activated AKT/mTOR and PDK1/MYC pathways and conferred considerable BEZ235 resistance in nasopharyngeal carcinoma. Targeting methyltransferases in combination with BEZ235 sensitized BEZ235-resistant cells to BEZ235 in vitro and in vivo, suggesting the potential clinical application of this strategy to overcome BEZ235 resistance.

Hypoxia reduces placental mTOR activation in a hypoxia-induced model of intrauterine growth restriction (IUGR)

“…These are both involved in the negative regulation of mTOR (Qian et al. ). Ppp2r2b activation is known to be involved in the negative control of cell growth and division.…”

“…Interestingly, we also observed increased expression of the Ppp2r2b and Prkag3 genes. These are both involved in the negative regulation of mTOR (Qian et al 2015). Ppp2r2b activation is known to be involved in the negative control of cell growth and division.…”

“…Ppp2r2b activation is known to be involved in the negative control of cell growth and division. It is also involved in the downregulation of mTOR activation (Qian et al 2015). Prkag3 is a regulatory subunit of the AMP-activated protein kinase (AMPK) and it plays a role in the regulation of energy metabolism in the cells (Milan et al 2000).…”

The emerging role of PI3K/AKT-mediated epigenetic regulation in cancer

“…Preclinical studies have found that nasopharyngeal cell lines resistant to the PI3K/mTOR inhibitor BEZ235 are characterized by low expression of PTEN and the PP2A subunit PPP2R2B as a result of promoter hypermethylation [48]. BEZ235 refractory cell lines were modestly re-sensitized with the addition of decitabine [48].…”

“…BEZ235 refractory cell lines were modestly re-sensitized with the addition of decitabine [48]. Further research suggests the importance of DNMT3b function in promoting mTORC2 activation in melanoma; genetic loss of DNMT3 expression results in promoter hypomethylation and increased expression of mir-196b, which targets the mTORC2 component RICTOR.…”