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

// Xiao-jun Qian 1, 2, * , Yun-tian Li 1, * , Yan Yu 1, * , Fen Yang 1, 3 , Rong Deng 1 , Jiao Ji 1 , Lin Jiao 1 , Xuan Li 1 , Rui-Yan Wu 1 , Wen-Dan Chen 1 , Gong-Kan Feng 1 , Xiao-Feng Zhu 1 1 State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Cancer Center, Sun Yat-sen University, Guangzhou 510060, China 2 Department of Oncology, Anhui Provincial Hospital, Affiliated to Anhui Medical University, Hefei 230001, China 3 Department of Biochemistry and Molecular Biology, Nanjing Medical University, Nanjing 210000, China * These authors have contributed equally to this work Correspondence to: Xiao-Feng Zhu, e-mail: zhuxfeng@mail.sysu.edu.cn Keywords: BEZ235, Acquired Resistance, DNA Methyltransferase, Nasopharyngeal Carcinoma Received: November 26, 2014      Accepted: December 31, 2014      Published: February 11, 2015 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.