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Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing
09:24

Generation of Microtumors Using 3D Human Biogel Culture System and Patient-derived Glioblastoma Cells for Kinomic Profiling and Drug Response Testing

Published on: June 9, 2016

Dynamic inhibition of ATM kinase provides a strategy for glioblastoma multiforme radiosensitization and growth

Sarah E Golding1, Elizabeth Rosenberg, Bret R Adams

  • 1Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, USA.

Cell Cycle (Georgetown, Tex.)
|February 29, 2012
PubMed

Insights

Targeting ATM kinase with KU-60019 radiosensitizes glioblastoma cells and inhibits growth, showing promise for combination therapy with temozolomide and radiation, with minimal impact on normal brain cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Radiotherapy

Background:

  • Glioblastoma multiforme (GBM) exhibits resistance to current treatments.
  • The DNA damage response (DDR) pathway, mediated by ATM kinase, contributes to radioresistance in cancer cells.

Purpose of the Study:

  • To investigate the efficacy of ATM kinase inhibition using KU-60019 as a radiosensitizing strategy for glioblastoma.
  • To evaluate the combination effects of KU-60019 with temozolomide (TMZ) and radiation therapy.

Main Methods:

  • Utilized a second-generation ATM inhibitor (KU-60019) to target ATM kinase in human glioblastoma cells.
  • Assessed inhibition of DDR signaling pathways (p53, H2AX, KAP1, AKT phosphorylation).
  • Performed colony-forming radiosurvival assays and co-treatment studies with KU-60019, TMZ, and radiation.

Main Results:

  • KU-60019 achieved rapid, reversible, and complete DDR inhibition at sub-micromolar concentrations.
  • Nanomolar concentrations of KU-60019 effectively radiosensitized glioblastoma cell lines.
  • Co-treatment with KU-60019 and TMZ showed a modest increase in radiation-induced cell killing.
  • KU-60019 alone or with TMZ reduced glioma cell growth without significantly affecting normal astrocytes.

Conclusions:

  • Transient ATM kinase inhibition is a promising strategy for enhancing glioblastoma radiosensitization in combination therapies.
  • KU-60019 demonstrates potential for limiting glioma cell growth with minimal toxicity to surrounding brain tissue, suggesting therapeutic applications beyond radiosensitization.

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