3129 - Inhibition of ATM and xCT Enhances Radiation Sensitivity and Suppresses Tumor Growth in Glioblastoma

05:00pm - 06:00pm PT

Hall F

Screen: 24

POSTER

Presenter(s)

Mi Youn Seol, MS - Yonsei University College of Medicine, Seoul,

M. Y. Seol Jr^1,2, S. Choi^1,2, and H. I. Yoon^1,2; ¹Yonsei University College of Medicine, Seoul, Korea, Republic of (South), ²Department of Radiation Oncology, Yonsei Cancer Center, Heavy Ion Therapy Research Institute, Yonsei University College of Medicine, Seoul, Korea, Republic of (South)

Purpose/Objective(s): Glioblastoma (GBM) is an aggressive brain cancer with a poor prognosis, where radioresistance remains a major challenge. Overcoming this resistance is crucial for improving treatment outcomes. Ataxia-telangiectasia mutated (ATM) serine/threonine protein kinase plays a crucial role in DNA double-strand break (DSB) repair, and its activation following irradiation contributes to radioresistance. Additionally, the cystine/glutamate antiporter (xCT), highly expressed in GBM, contributes to tumor malignancy and therapy resistance by enhancing tumor survival under oxidative stress. Given their roles, ATM and xCT are promising therapeutic targets for overcoming radioresistance. This study examines whether their simultaneous inhibition, combined with irradiation, improves radiosensitivity and suppresses tumor growth in GBM.

Materials/Methods: We used the Glioma 261 luciferase-expressing (GL261-luc) cell line to assess the effects of combination therapy. GL261-luc cells were irradiated with 1 Gy, with or without ATM and xCT inhibitors. After irradiation, cell survival was evaluated using a clonogenic assay, and inhibition of ATM and xCT signaling pathways was confirmed via Western blot (WB) assay. To assess the repair of DNA DSBs, the expression of phospho-H2A.X was examined by immunofluorescence. Additionally, to investigate the effects of combination therapy in vivo, the stereotactic mouse model was established by intracranial injection of GL261-luc. Irradiation was specifically administered to brain with 2 Gy per day for five consecutive days, with or without ATM inhibitors (AZD0156, AZD1390, 1 mg/kg) and the xCT inhibitor sulfasalazine (100 mg/kg). Tumor growth was monitored using IVIS imaging.

Results: GL261-luc irradiated with each inhibition of ATM and xCT by 1 Gy was suppressed cell growth compared to control. Simultaneous inhibition of ATM and xCT significantly increased GL261-luc radiosensitivity and markedly suppressed cell growth and survival rate was about 40% (p<00001). Additionally, radiotherapy with simultaneous inhibition of xCT and ATM markedly increased the expression of phospho-H2A.X, DNA DSB marker more than when xCT and ATM were inhibited alone. Each inhibition of ATM and xCT increased the radiosensitivity of brain tumors and suppressed tumor growth compared to control group in vivo. In particular, when ATM and xCT were simultaneously inhibited, brain tumors growth was markedly suppressed.

Conclusion: Our study demonstrated that the simultaneous inhibition of ATM and xCT significantly enhanced the radiosensitivity of GBM both in vitro and in vivo. Furthermore, GBM tumor growth was markedly suppressed with this approach. These findings suggest that radiotherapy combined with ATM and xCT inhibition may serve as a promising strategy for overcoming radioresistance in GBM and improving therapeutic outcomes. Further studies are warranted to validate these results.