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

Xiao-Jun Qian,Fen Yang,Wen-Dan Chen,Gong-Kan Feng,Lin Jiao,Rui-Yan Wu,Rong Deng,Xiao-Feng Zhu,Xuan Li,Yun-Tian Li,Jiao Ji,Yan Yu

doi:10.18632/oncotarget.3016

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.

Highlights

Targeted therapies might represent the future of personalized medicine for cancer patients
Reduced PTEN and PPP2R2B expression correlated with activated AKT/mTOR and PDK1/MYC pathways and conferred considerable BEZ235 resistance in nasopharyngeal carcinoma
We modeled the development of acquired resistance in patients by treating PIK3CA mutant nasopharyngeal carcinoma cells (CNE2, HONE1) with increasing doses of BEZ235 for 6 to 9 months to select BEZ235-resistant sublines (CNE2/235, HONE1/235) (Supplementary Table S1)

Summary

Introduction

Targeted therapies might represent the future of personalized medicine for cancer patients. The phosphatidylinositol 3-kinase (PI3K)-AKT pathway is one of the most commonly deregulated signaling pathways in human cancers [1]. It has been reported that BEZ235, one of the dual PI3K/mTOR(phosphatidylinositol 3-kinase/mammalian target of rapamycin) inhibitors, has a potent inhibitory effect in numerous tumors such as breast cancer [3], hepatic carcinoma [4], ovarian carcinoma [5], prostate cancer [6], medulloblastoma [7], non-small cell lung cancer [8, 9], non-Hodgkin lymphoma [10, 11], liposarcoma [12], cholangiocarcinoma [13], leukemia [14], pancreatic cancer [15, 16] and nasopharyngeal carcinoma [17] in preclinical studies, especially in PIK3CA mutant subtypes. BEZ235 significantly inhibits cell proliferation in nasopharyngeal carcinoma both in vitro and in vivo by blocking the PI3K/AKT/mTOR pathway [17, 19]

Methods

Results

Conclusion