Predictability, efficacy and safety of radiosensitization of glioblastoma-initiating cells by the ATM inhibitor KU-60019

摘要

We have previously shown that pharmacological inhibition of ataxia telangiectasia mutated (ATM) protein sensitizes glioblastoma-initiating cells (GICs) to ionizing radiation (IR). Herein, we report the experimental conditions to overcome GIC radioresistance in vitro using the specific ATM inhibitor KU-60019, two major determinants of the tumor response to this drug and the absence of toxicity of this treatment in vitro and in vivo. Repeated treatments with KU-60019 followed by IR substantially delayed GIC proliferation in vitro and even eradicated radioresistant cells, whereas GIC treated with vehicle plus radiation recovered early and expanded. The tumor response to the drug occurred under a cutoff level of expression of TP53 and over a cutoff level of expression of phosphatidylinositol 3-kinase (PI3K). No increased clastogenicity or point mutagenicity was induced by KU-60019 plus radiation when compared to vehicle plus radiation. No significant histological changes to the brain or other organs were observed after prolonged infusion into the brain of KU-60019 at millimolar concentrations. Taken together, these findings suggest that GIC-driven tumors with low expression of TP53 and high expression of PI3K might be effectively and safely radiosensitized by KU-60019. What's new? Glioblastoma multiforme is a highly infiltrative brain tumor resistant to radiation. Here, the authors report that inhibition of Ataxia Telangiectasia Mutated (ATM) protein, a key regulator of the DNA damage checkpoint response, improves the efficacy of ionizing radiation against radio-resistant glioblastoma-initiating cells, primary human cell lines isolated from grade IV gliomas. The response to the ATM inhibitor KU-60019 correlated with low expression levels of tumor protein p53 (wild type or mutant) and high expression levels of phosphatidylinositol 3-kinase and was tested after intracranial application in mice with orthotopic tumors. The study supports emerging evidence that KU-60019 may improve radiotherapy of high-grade gliomas.