ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells

Aditi Nadkarni, Meena Shrivastav, Ann C. Mladek, Paul M. Schwingler, Patrick T. Grogan, Junjie Chen, Jann N. Sarkaria

Research output: Contribution to journalArticle

35 Scopus citations

Abstract

Ataxia telangiectasia mutated (ATM) kinase is critical in sensing and repairing DNA double-stranded breaks (DSBs) such as those induced by temozolomide (TMZ). ATM deficiency increases TMZ sensitivity, which suggests that ATM inhibitors may be effective TMZ sensitizing agents. In this study, the TMZ sensitizing effects of 2 ATM specific inhibitors were studied in established and xenograft-derived glioblastoma (GBM) lines that are inherently sensitive to TMZ and derivative TMZ-resistant lines. In parental U251 and U87 glioma lines, the addition of KU-55933 to TMZ significantly increased cell killing compared to TMZ alone [U251 survival: 0.004 ± 0.0015 vs. 0.08 ± 0.01 (p<0.001), respectively, and U87 survival: 0.02 ± 0.005 vs. 0.04 ± 0.002 (p<0.001), respectively] and also elevated the fraction of cells arrested in G2/M [U251 G2/M fraction: 61.8 ± 1.1 % vs. 35 ± 0.8 % (p<0.001), respectively, and U87 G2/M fraction 25 ± 0.2 %vs.18.6 ± 0.4 %(p<0.001), respectively]. In contrast, KU-55933 did not sensitize the resistant lines to TMZ, and neither TMZ alone or combined with KU-55933 induced a G2/M arrest. While KU-55933 did not enhance TMZ induced Chk1/Chk2 activation, it increased TMZ-induced residual γ-H2AX foci in the parental cells but not in the TMZ resistant cells. Similar sensitization was observed with either KU-55933 or CP-466722 combined with TMZ in GBM12 xenograft line but not in GBM12TMZ, which is resistant to TMZ due to MGMT overexpression. These findings are consistent with a model where ATM inhibition suppresses the repair of TMZ-induced DSBs in inherently TMZ-sensitive tumor lines, which suggests an ATMinhibitor potentially could be deployed with an improvement in the therapeutic window when combined with TMZ.

Original languageEnglish (US)
Pages (from-to)349-357
Number of pages9
JournalJournal of neuro-oncology
Volume110
Issue number3
DOIs
StatePublished - Dec 2012

Keywords

  • ATM inhibitor
  • DNA repair
  • Glioblastoma
  • Temozolomide

ASJC Scopus subject areas

  • Oncology
  • Neurology
  • Clinical Neurology
  • Cancer Research

Fingerprint Dive into the research topics of 'ATM inhibitor KU-55933 increases the TMZ responsiveness of only inherently TMZ sensitive GBM cells'. Together they form a unique fingerprint.

  • Cite this