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Poster De Conférence Année : 2023

Atr kinase inhibitor augments ifn signaling following proton and carbon ion irradiation

Résumé

Conventional radiotherapy (X-ray irradiation) plays a crucial role in glioblastoma standard treatment, but is limited by tumor radioresistance and damage to the normal brain. The treatment with charged particle has shown better specificity and lower toxicity for the surrounding normal tissue due to their beneficial depth-dose distribution. To further challenge the repair capacity of tumor cells, radiation can be combined with DNA-damage response inhibitors. Such combinations may cause cells to enter mitosis with higher amount of unrepaired damaged DNA leading to formation of micronuclei. DNA from these micronuclei may be exposed to the cytosol and trigger an innate antitumor immune response. However, to what extent such immune responses are induced for protons and heavy ions, is largely unknown. Here we addressed the DNA-damage response in cells exposed to high or low LET charged particle irradiation and investigated cell cycle progression and immune activation upon co-treatment with inhibitors of the DNA-damage response proteins ATM and ATR (AZD1390 and VE822, respectively). T98G or U-251MG glioblastoma cell lines were irradiated (2-6 Gy) with experimental proton and carbon ion beams having energies of 17 MeV and 95 MeV, respectively. LETs for protons were 7 and 38 keV/μm and for carbon ions 28 and 73 keV/μm. Assessment of the DNA-damage marker γH2AX and cell cycle distribution by flow cytometry showed more damage and a stronger G2 checkpoint induction by high compared to low LET protons for the same radiation dose. Immunoblotting for phosphorylated CHK1 S317 and S345, and ATM S1981 also showed a more robust activation of ATR and ATM in response to high compared to low LET protons. Similar differences were obtained for carbon ions. Furthermore, co-treatment with the ATR inhibitor abrogated the G2 checkpoint and led to increased interferon production at both high and low LET, as measured by immunoblotting of pSTAT three days after treatment in U-251. In contrast, co-treatment with an ATM inhibitor caused a prolonged G2 checkpoint and gave little increase in interferon levels. These outcomes show a LET-dependent DNA-damage response in glioblastoma, and suggest that ATR inhibition can increase interferon signaling in both high and low LET particle irradiated cells, likely through abrogation of the G2 checkpoint.
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Dates et versions

hal-04217114 , version 1 (25-09-2023)

Identifiants

  • HAL Id : hal-04217114 , version 1

Citer

Diana Iulia. Savu, Gro Elise Rødland, Mihaela Temelie, Ana-Maria Serban, Adrian E. Mariampillai, et al.. Atr kinase inhibitor augments ifn signaling following proton and carbon ion irradiation. ICRR 2023, Aug 2023, Montréal Québec, Canada. ⟨hal-04217114⟩
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