TY - JOUR
T1 - ABT-888 restores sensitivity in temozolomide resistant glioma cells and xenografts
AU - Yuan, Alice L.
AU - Ricks, Christian B.
AU - Bohm, Alexandra K.
AU - Lun, Xueqing
AU - Maxwell, Lori
AU - Safdar, Shahana
AU - Bukhari, Shazreh
AU - Gerber, Amanda
AU - Sayeed, Wajid
AU - Bering, Elizabeth A.
AU - Pedersen, Haley
AU - Chan, Jennifer A.
AU - Shen, Yaoqing
AU - Marra, Marco
AU - Kaplan, David R.
AU - Mason, Warren
AU - Goodman, Lindsey D.
AU - Ezhilarasan, Ravesanker
AU - Kaufmann, Ascher B.
AU - Cabral, Matthew
AU - Robbins, Steve M.
AU - Senger, Donna L.
AU - Cahill, Daniel P.
AU - Sulman, Erik P.
AU - Gregory Cairncross, J.
AU - Blough, Michael D.
N1 - Publisher Copyright:
© 2018 Yuan et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2018/8
Y1 - 2018/8
N2 - Background Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylgua-nine-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.
AB - Background Temozolomide (TMZ) is active against glioblastomas (GBM) in which the O6-methylgua-nine-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.
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U2 - 10.1371/journal.pone.0202860
DO - 10.1371/journal.pone.0202860
M3 - Article
C2 - 30153289
AN - SCOPUS:85052574902
SN - 1932-6203
VL - 13
JO - PloS one
JF - PloS one
IS - 8
M1 - e0202860
ER -