ArticleCancer research2021
Inhibition of ATM Induces Hypersensitivity to Proton Irradiation by Upregulating Toxic End Joining.
Article in Cancer research, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 26 papers.
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Who cites it
26 citing papers in PubMed, 45 citations in OpenAlex.
- Review
- Review
- Poly ADP Ribose Polymerase Inhibitors Potentiate Proton Therapy End-of-Range Effects by Accelerating Replication Forks and Promoting Transcription Conflict.International journal of radiation oncology, biology, physics · 2026Article
- Article
- CRISPR/Cas9 generated DSB clusters mimic complex lesions induced by high-LET radiation and shift repair from c-NHEJ to mutagenic repair pathways.Scientific reports · 2025Article
- Dual ENPP1/ATM depletion blunts DNA damage repair boosting radioimmune efficacy to abrogate triple-negative breast cancer.Signal transduction and targeted therapy · 2025Article
- Particle Therapy to Overcome Cancer Radiation Resistance: "ARCHADE" Consortium Updates in Radiation Biology.Cancers · 2025Review
- Enhanced radiosensitivity of head and neck cancer cells to proton therapy via hyperthermia-induced homologous recombination deficiency.Clinical and translational radiation oncology · 2025Article
- Position in proton Bragg curve influences DNA damage complexity and survival in head and neck cancer cells.Clinical and translational radiation oncology · 2025Article
- NRG Oncology White Paper on the Relative Biological Effectiveness in Proton Therapy.International journal of radiation oncology, biology, physics · 2025Review
- PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy.Scientific reports · 2024Article
- ATR inhibition radiosensitizes cells through augmented DNA damage and G2 cell cycle arrest abrogation.JCI insight · 2024Article
- Proton therapy for breast cancer: Reducing toxicity.Thoracic cancer · 2024Review
- Potential Benefits of Combining Proton or Carbon Ion Therapy with DNA Damage Repair Inhibitors.Cells · 2024Review
- Syk-dependent homologous recombination activation promotes cancer resistance to DNA targeted therapy.Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy · 2024Article
- Synergistic Activity of DNA Damage Response Inhibitors in Combination with Radium-223 in Prostate Cancer.Cancers · 2024Article
- Safety of the Breast Cancer Adjuvant Radiotherapy in Ataxia-Telangiectasia Mutated Variant Carriers.Cancers · 2024Article
- Targeting OGG1 and PARG radiosensitises head and neck cancer cells to high-LET protons through complex DNA damage persistence.Cell death & disease · 2024Article
- Key molecular DNA damage responses of human cells to radiation.Frontiers in cell and developmental biology · 2024Review
- DNA damage and repair dependencies of ionising radiation modalities.Bioscience reports · 2023Review
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Authors and funding
17 authors at 2 institutions in 1 country.
Funding
Abstract
Proton Bragg peak irradiation has a higher ionizing density than conventional photon irradiation or the entrance of the proton beam profile. Whether targeting the DNA damage response (DDR) could enhance vulnerability to the distinct pattern of damage induced by proton Bragg peak irradiation is currently unknown. Here, we performed genetic or pharmacologic manipulation of key DDR elements and evaluated DNA damage signaling, DNA repair, and tumor control in cell lines and xenografts treated with the same physical dose across a radiotherapy linear energy transfer spectrum. Radiotherapy consisted of 6 MV photons and the entrance beam or Bragg peak of a 76.8 MeV spot scanning proton beam. More complex DNA double-strand breaks (DSB) induced by Bragg peak proton irradiation preferentially underwent resection and engaged homologous recombination (HR) machinery. Unexpectedly, the ataxia-telangiectasia mutated (ATM) inhibitor, AZD0156, but not an inhibitor of ATM and Rad3-related, rendered cells hypersensitive to more densely ionizing proton Bragg peak irradiation. ATM inhibition blocked resection and shunted more DSBs to processing by toxic ligation through nonhomologous end-joining, whereas loss of DNA ligation via XRCC4 or Lig4 knockdown rescued resection and abolished the enhanced Bragg peak cell killing. Proton Bragg peak monotherapy selectively sensitized cell lines and tumor xenografts with inherent HR defects, and the repair defect induced by ATM inhibitor coadministration showed enhanced efficacy in HR-proficient models. In summary, inherent defects in HR or administration of an ATM inhibitor in HR-proficient tumors selectively enhances the relative biological effectiveness of proton Bragg peak irradiation. SIGNIFICANCE: Coadministration of an ATM inhibitor rewires DNA repair machinery to render cancer cells uniquely hypersensitive to DNA damage induced by the proton Bragg peak, which is characterized by higher density ionization.
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