Inhibition of DNA Methyltransferase As a Novel Therapeutic Strategy to Overcome Acquired Resistance to Dual PI3K/mTOR Inhibitors

Overview

Journal Oncotarget

Specialty Oncology

Date 2015 Mar 13

PMID 25762617

Citations 24

Authors

Xiao-Jun Qian

Yun-Tian Li

Yan Yu

Fen Yang

Rong Deng

Jiao Ji

Lin Jiao

Xuan Li

Rui-Yan Wu

Wen-Dan Chen

Gong-Kan Feng

Xiao-Feng Zhu

Affiliations

Soon will be listed here.

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.

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