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

Oncotarget
Xiao-jun QianXiao-Feng Zhu

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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Citations

Aug 28, 2020·Frontiers in Oncology·Susana Romero-GarciaAngeles Carlos-Reyes
Jun 24, 2017·Modern Pathology : an Official Journal of the United States and Canadian Academy of Pathology, Inc·Stephen J MurphyEva M Carmona
May 22, 2020·Proceedings of the National Academy of Sciences of the United States of America·Wei-Cheng LuEverett Stone
Sep 17, 2020·Journal of Clinical Medicine·Salihanur DariciXu Huang
Feb 21, 2019·Molecular Cancer·Jing YangXiawei Wei
Apr 4, 2021·International Journal of Molecular Sciences·Rosalin MishraJoan T Garrett

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Methods Mentioned

BETA
flow cytometry
Chip
PCR
immunoprecipitation
transfection
immunoprecipitation assay
Xenograft
xenografts
dissection
fluorescence activated cell sorting

Software Mentioned

Cytomics RXP Analysis

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