ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts

PLoS One. 2018 Aug 28;13(8):e0202860. doi: 10.1371/journal.pone.0202860. eCollection 2018.

Abstract

Background: Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylguanine-DNA methyltransferase (MGMT) gene is silenced. However, even in responsive cases, its beneficial effect is undermined by the emergence of drug resistance. Here, we tested whether inhibition of poly (ADP-ribose) polymerase-1 and -2 (PARP) enhanced the effectiveness of TMZ.

Methods: Using patient derived brain tumor initiating cells (BTICs) and orthotopic xenografts as models of newly diagnosed and recurrent high-grade glioma, we assessed the effects of TMZ, ABT-888, and the combination of TMZ and ABT-888 on the viability of BTICs and survival of tumor-bearing mice. We also studied DNA damage repair, checkpoint protein phosphorylation, and DNA replication in mismatch repair (MMR) deficient cells treated with TMZ and TMZ plus ABT-888.

Results: Cells and xenografts derived from newly diagnosed MGMT methylated high-grade gliomas were sensitive to TMZ while those derived from unmethylated and recurrent gliomas were typically resistant. ABT-888 had no effect on the viability of BTICs or tumor bearing mice, but co-treatment with TMZ restored sensitivity in resistant cells and xenografts from newly diagnosed unmethylated gliomas and recurrent gliomas with MSH6 mutations. In contrast, the addition of ABT-888 to TMZ had little sensitizing effect on cells and xenografts derived from newly diagnosed methylated gliomas. In a model of acquired TMZ resistance mediated by loss of MMR gene MSH6, re-sensitization to TMZ by ABT-888 was accompanied by persistent DNA strand breaks, re-engagement of checkpoint kinase signaling, and interruption of DNA synthesis.

Conclusion: In laboratory models, the addition of ABT-888 to TMZ overcame resistance to TMZ.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Benzimidazoles / pharmacology*
  • Cell Line, Tumor
  • DNA-Binding Proteins / deficiency
  • DNA-Binding Proteins / genetics
  • Drug Resistance, Neoplasm / drug effects*
  • Female
  • Gene Knockdown Techniques
  • Glioma / pathology*
  • Humans
  • Mice
  • Neoplasm Grading
  • RNA, Small Interfering / genetics
  • Temozolomide / pharmacology*
  • Xenograft Model Antitumor Assays*

Substances

  • Benzimidazoles
  • DNA-Binding Proteins
  • G-T mismatch-binding protein
  • RNA, Small Interfering
  • veliparib
  • Temozolomide

Grant support

This work was supported by the Terry Fox Research Institute and Foundation (CA), the Alberta Cancer Foundation, Genome Canada, Alberta Innovates Health Solutions all to MDB, and the family of Clark H. Smith. DPC is the recipient of a Burroughs Wellcome Career Award. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.