The DOI matches its Crossref record; 9 of the 9 references it cites were found in a registry or an index.
Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells
Abstract
Glioblastoma is the most common form of primary brain tumor in adults and is essentially incurable. Despite aggressive treatment regimens centered on radiotherapy, tumor recurrence is inevitable and is thought to be driven by glioblastoma stem-like cells (GSC) that are highly radioresistant. DNA damage response pathways are key determinants of radiosensitivity but the extent to which these overlapping and parallel signaling components contribute to GSC radioresistance is unclear. Using a panel of primary patient-derived glioblastoma cell lines, we confirmed by clonogenic survival assays that GSCs were significantly more radioresistant than paired tumor bulk populations. DNA damage response targets ATM, ATR, CHK1, and PARP1 were upregulated in GSCs, and CHK1 was preferentially activated following irradiation. Consequently, GSCs exhibit rapid G2–M cell-cycle checkpoint activation and enhanced DNA repair. Inhibition of CHK1 or ATR successfully abrogated G2–M checkpoint function, leading to increased mitotic catastrophe and a modest increase in radiation sensitivity. Inhibition of ATM had dual effects on cell-cycle checkpoint regulation and DNA repair that were associated with greater radiosensitizing effects on GSCs than inhibition of CHK1, ATR, or PARP alone. Combined inhibition of PARP and ATR resulted in a profound radiosensitization of GSCs, which was of greater magnitude than in bulk populations and also exceeded the effect of ATM inhibition. These data demonstrate that multiple, parallel DNA damage signaling pathways contribute to GSC radioresistance and that combined inhibition of cell-cycle checkpoint and DNA repair targets provides the most effective means to overcome radioresistance of GSC. Cancer Res; 75(20); 4416–28. ©2015 AACR.
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Cites
Comprehensive genomic characterization defines human glioblastoma genes and core pathways
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DNA damage response as a candidate anti-cancer barrier in early human tumorigenesis
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A restricted cell population propagates glioblastoma growth after chemotherapy
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ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks
Jazayeri, A., Falck, J., Lukas, C., Bartek, J., Smith, G. C. M., Lukas, J., & Jackson, S. P. (2006) · Nature Cell Biology · doi:10.1038/ncb1337 · Cited by 1,064
Glioblastoma Stem Cells Generate Vascular Pericytes to Support Vessel Function and Tumor Growth
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PARP-1 protein expression in glioblastoma multiforme
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Cited by
Glioblastoma Stem Cells: Driving Resilience through Chaos
Prager, B. C., Bhargava, S., Mahadev, V., Hubert, C. G., & Rich, J. N. (2020) · Trends in Cancer · doi:10.1016/j.trecan.2020.01.009 · Cited by 401
Vitale, I., Manic, G., De Maria, R., Kroemer, G., & Galluzzi, L. (2017) · Molecular Cell · doi:10.1016/j.molcel.2017.04.006 · Cited by 361
Krause, M., Dubrovska, A., Linge, A., & Baumann, M. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2016.02.002 · Cited by 305
Cancer Stem Cells and Radioresistance: DNA Repair and Beyond
Schulz, A., Meyer, F., Dubrovska, A., & Borgmann, K. (2019) · Cancers · doi:10.3390/cancers11060862 · Cited by 303
Glioblastoma Therapy: Past, Present and Future
Obrador, E., Moreno-Murciano, P., Oriol-Caballo, M., López-Blanch, R., Pineda, B., Gutiérrez-Arroyo, J., Loras, A., Gonzalez-Bonet, L., Martinez-Cadenas, C., Estrela, J., et al. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25052529 · Cited by 271
Metadata
- Authors
- Ahmed, S. U., Carruthers, R., Gilmour, L., Yildirim, S., Watts, C., & Chalmers, A. J.
- Venue
- Cancer Research
- Published
- 2015-10-14
- Volume
- 75
- Issue
- 20
- Pages
- 4416-4428
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2165400661
- Cited by
- 194
- References
- 9
- FWCI
- 7.83
- Type
- journal article
- Language
- en
- Open access
- closed
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- Ahmed, S. U., Carruthers, R., Gilmour, L., Yildirim, S., Watts, C., & Chalmers, A. J. (2015). Selective Inhibition of Parallel DNA Damage Response Pathways Optimizes Radiosensitization of Glioblastoma Stem-like Cells. Cancer Research. https://doi.org/10.1158/0008-5472.can-14-3790
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