ArticleClinical cancer research : an official journal of the American Association for Cancer Research2014
Inhibition of DNA double-strand break repair by the dual PI3K/mTOR inhibitor NVP-BEZ235 as a strategy for radiosensitization of glioblastoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 101 papers.
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Who cites it
101 citing papers in PubMed, 169 citations in OpenAlex.
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- Prodigiosin in glioblastoma: mechanistic pharmacology and rationale for its development as a radiosensitiser.Frontiers in pharmacology · 2026Review
- A Comprehensive Analysis of Natural Bioactive Molecules for the Treatment and Control of Glioblastoma Multiforme (GBM) Targeting Underlying Molecular Mechanism.Chemistry & biodiversity · 2026Review
- mTOR signaling networks: mechanistic insights and translational frontiers in disease therapeutics.Signal transduction and targeted therapy · 2025Review
- Par6/SOX2 interact to modulate stemness maintenance in glioma by regulating the EGFR/PI3K/AKT signaling cascade.Oncogene · 2025Article
- Revisiting an old therapy for new, promising combinations: Biology and perspectives of lomustine in glioma treatment.Neuro-oncology · 2025Review
- BUB1B promotes homologous recombination‑mediated DNA damage repair in breast cancer cells through the PI3K/AKT signaling pathway.Oncology reports · 2025Article
- Beyond base camp: PI3K/mTOR inhibition for the treatment of pediatric high-grade gliomas.Neuro-oncology · 2025Review
- Inhibition of ATM enhances the immunogenicity of triple-negative breast cancer by promoting MHC-I expression.Cell death & disease · 2025Article
- Beyond Base Camp: Promise and Pitfalls of PI3K/mTOR Inhibition in Pediatric High- Grade Gliomas.Research square · 2025Article
- Combined inhibition of class 1-PI3K-alpha and delta isoforms causes senolysis by inducing p21Cell death & disease · 2024Article
- DBDNMF: A Dual Branch Deep Neural Matrix Factorization method for drug response prediction.PLoS computational biology · 2024Article
- Multiplex single-cell chemical genomics reveals the kinase dependence of the response to targeted therapy.Cell genomics · 2024Article
- Myriad factors and pathways influencing tumor radiotherapy resistance.Open life sciences · 2024Review
- Establishment and Application of Novel Hypoxia-driven Dual-reporter Model to Investigate Hypoxic Impact on Radiation Sensitivity in Human Nasopharyngeal Carcinoma Xenografts.Journal of Cancer · 2024Article
- Unveiling Novel Avenues in mTOR-Targeted Therapeutics: Advancements in Glioblastoma Treatment.International journal of molecular sciences · 2023Review
- Radiation-induced tumor immune microenvironments and potential targets for combination therapy.Signal transduction and targeted therapy · 2023Review
- PI3K/AKT/mTOR Signaling Pathway in HPV-Driven Head and Neck Carcinogenesis: Therapeutic Implications.Biology · 2023Review
- PI3K/AKT/mTOR pathway, hypoxia, and glucose metabolism: Potential targets to overcome radioresistance in small cell lung cancer.Cancer pathogenesis and therapy · 2023Review
41 more citing papers are in PubMed but not listed here.
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Authors and funding
11 authors at 3 institutions in 1 country.
Funding
Abstract
purposeInhibitors of the DNA damage response (DDR) have great potential for radiosensitization of numerous cancers, including glioblastomas, which are extremely radio- and chemoresistant brain tumors. Currently, there are no DNA double-strand break (DSB) repair inhibitors that have been successful in treating glioblastoma. Our laboratory previously demonstrated that the dual phosphoinositide 3-kinase/mTOR inhibitor NVP-BEZ235 can potently inhibit the two central DDR kinases, DNA-dependent protein kinase catalytic subunit (DNA-PKcs) and ataxia-telangiectasia mutated (ATM), in vitro. Here, we tested whether NVP-BEZ235 could also inhibit ATM and DNA-PKcs in tumors in vivo and assessed its potential as a radio- and chemosensitizer in preclinical mouse glioblastoma models. EXPERIMENTAL
designThe radiosensitizing effect of NVP-BEZ235 was tested by following tumor growth in subcutaneous and orthotopic glioblastoma models. Tumors were generated using the radioresistant U87-vIII glioma cell line and GBM9 neurospheres in nude mice. These tumors were then treated with ionizing radiation and/or NVP-BEZ235 and analyzed for DNA-PKcs and ATM activation, DSB repair inhibition, and attenuation of growth.
resultsNVP-BEZ235 potently inhibited both DNA-PKcs and ATM kinases and attenuated the repair of ionizing radiation-induced DNA damage in tumors. This resulted in striking tumor radiosensitization, which extended the survival of brain tumor-bearing mice. Notably, tumors displayed a higher DSB-load when compared with normal brain tissue. NVP-BEZ235 also sensitized a subset of subcutaneous tumors to temozolomide, a drug routinely used concurrently with ionizing radiation for the treatment of glioblastoma.
conclusionsThese results demonstrate that it may be possible to significantly improve glioblastoma therapy by combining ionizing radiation with potent and bioavailable DNA repair inhibitors such as NVP-BEZ235.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.