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

Oncotarget. 2015 Mar 10;6(7):5134-46. 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.

Keywords: BEZ235; DNA methyltransferase; acquired resistance; nasopharyngeal carcinoma.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis
  • Blotting, Western
  • Cell Cycle
  • Cell Proliferation
  • DNA (Cytosine-5-)-Methyltransferases / antagonists & inhibitors*
  • DNA (Cytosine-5-)-Methyltransferases / genetics
  • DNA (Cytosine-5-)-Methyltransferases / metabolism
  • DNA Methylation
  • Drug Resistance, Neoplasm / drug effects*
  • Enzyme Inhibitors / pharmacology*
  • Female
  • Humans
  • Imidazoles / pharmacology
  • Immunoenzyme Techniques
  • Mice
  • Mice, Inbred BALB C
  • Mice, Nude
  • Nasopharyngeal Neoplasms / drug therapy*
  • Nasopharyngeal Neoplasms / metabolism
  • Nasopharyngeal Neoplasms / pathology
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism
  • PTEN Phosphohydrolase / genetics
  • PTEN Phosphohydrolase / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Phosphatidylinositol 3-Kinases / metabolism*
  • Phosphoinositide-3 Kinase Inhibitors
  • Protein Phosphatase 2 / genetics
  • Protein Phosphatase 2 / metabolism
  • Protein Serine-Threonine Kinases / genetics
  • Protein Serine-Threonine Kinases / metabolism
  • Proto-Oncogene Proteins c-myc / genetics
  • Proto-Oncogene Proteins c-myc / metabolism
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Quinolines / pharmacology
  • RNA, Messenger / genetics
  • Real-Time Polymerase Chain Reaction
  • Reverse Transcriptase Polymerase Chain Reaction
  • TOR Serine-Threonine Kinases / antagonists & inhibitors
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Tumor Cells, Cultured
  • Xenograft Model Antitumor Assays

Substances

  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Imidazoles
  • MYC protein, human
  • Nerve Tissue Proteins
  • PDK1 protein, human
  • Pdk1 protein, mouse
  • Phosphoinositide-3 Kinase Inhibitors
  • Proto-Oncogene Proteins c-myc
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Quinolines
  • RNA, Messenger
  • DNA (Cytosine-5-)-Methyltransferases
  • MTOR protein, human
  • Protein Serine-Threonine Kinases
  • TOR Serine-Threonine Kinases
  • PPP2R2B protein, human
  • Protein Phosphatase 2
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • dactolisib