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

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

Author information

1
Clark H. Smith Brain Tumour Centre, University of Calgary, Calgary, Alberta, Canada.
2
Charbonneau Cancer Institute, University of Calgary, Calgary, Alberta, Canada.
3
Department of Radiation Oncology, MD Anderson Cancer Center, Houston, Texas, United States of America.
4
Department of Oncology, University of Calgary, Calgary, Alberta, Canada.
5
Department of Pathology & Laboratory Medicine, University of Calgary, Calgary, Alberta, Canada.
6
Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, British Columbia, Canada.
7
Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada.
8
Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, Ontario, Canada.
9
Princess Margaret Cancer Centre, Toronto, Ontario, Canada.
10
Department of Neurosurgery, MD Anderson Cancer Center, Houston, Texas, United States of America.
11
Department of Neurosurgery, Massachusetts General Hospital, Boston, Massachusetts, United States of America.
12
Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada.
13
Hotchkiss Brain Institute, University of Calgary, Calgary, Alberta, Canada.

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.

PMID:
30153289
PMCID:
PMC6112648
DOI:
10.1371/journal.pone.0202860
[Indexed for MEDLINE]
Free PMC Article

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