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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