ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts
2018
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 initiatingcells (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
gliomaswere sensitive to TMZ while those derived from unmethylated and recurrent
gliomaswere 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
gliomasand recurrent
gliomaswith
MSH6mutations. 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.
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