Abstract
Primary treatment modality for glioblastoma (GBM) post-surgery is radiation therapy. Due to increased DNA damage repair capacity of resistant residual GBM cells, recurrence is inevitable in glioblastoma and unfortunately the recurrent tumours are resistant to the conventional therapy. Here we used our previously described in vitro radiation survival model generated from primary GBM patient samples and cell lines, which recapitulates the clinical scenario of therapy resistance and relapse. Using the parent and recurrent GBM cells from these models, we show that similar to parent GBM, the recurrent GBM cells also elicit a competent DNA damage response (DDR) post irradiation. However, the use of apical DNA damage repair sensory kinase (ATM and/or ATR) is different in the recurrent cells compared to parent cells. Consistently, we demonstrate that there is a differential clonogenic response of parent and recurrent GBM cells to the ATM and ATR kinase inhibitors with recurrent samples switching between these sensory kinases for survival emphasizing on the underlying heterogeneity within and across GBM samples. Taken together, here we report that recurrent tumours utilize an alternate DDR kinase to overcome radiation induced DNA damage. Since there is no effective treatment specifically for recurred GBM patients, these findings provide a rationale for developing newer treatment option to sensitize recurrent GBM samples by detecting in clinics the ability of cells to activate a DNA damage repair kinase different from their parent counterparts.
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Acknowledgements
This work was supported by Department of Biotechnology (BT/PR4020/MED/30/792/2012) to SD. EK is Council of Scientific and Industrial Research (CSIR) Fellow. Immunofluorescence images were captured with the help from ACTREC Digital Imaging facility (ADIF).
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SD and EK conceptualized and designed the experiments. EK and MK performed the experiments. EK, MK and SD analysed data and prepared the manuscript. SD supervised research.
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GBM tissues were obtained after approval from the Tata Memorial Centre Institutional Ethics Committee (TMC-IEC III) DCGI registration number: IEC III: ECR/149/Inst/MH/2013 and after obtaining a written consent form in the language understood by the patients.
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Kaur, E., Ketkar, M. & Dutt, S. Glioblastoma recurrent cells switch between ATM and ATR pathway as an alternative strategy to survive radiation stress. Med Oncol 39, 50 (2022). https://doi.org/10.1007/s12032-022-01657-4
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DOI: https://doi.org/10.1007/s12032-022-01657-4