PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy
Abstract Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that gen...
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| Format: | Article |
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Nature Portfolio
2024-12-01
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| Series: | Scientific Reports |
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| Online Access: | https://doi.org/10.1038/s41598-024-81914-w |
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| author | Mariam Ben Kacem Scott J. Bright Emma Moran David B. Flint David K. J. Martinus Broderick X. Turner Ilsa Qureshi Rishab Kolachina Mandira Manandhar Poliana C. Marinello Simona F. Shaitelman Gabriel O. Sawakuchi |
| author_facet | Mariam Ben Kacem Scott J. Bright Emma Moran David B. Flint David K. J. Martinus Broderick X. Turner Ilsa Qureshi Rishab Kolachina Mandira Manandhar Poliana C. Marinello Simona F. Shaitelman Gabriel O. Sawakuchi |
| author_sort | Mariam Ben Kacem |
| collection | DOAJ |
| description | Abstract Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons and protons (9.9 and 3.85 keV/µm) independent of BRCA1 status. Numbers of γH2AX foci, micronuclei, and cGAS-positive micronuclei were significantly higher in BRCA1-mutated cells. Cell cycle distribution and stress-induced senescence were not affected by PARP inhibition in our cell lines. In vivo, the combination of protons (3.99 keV/µm) and PARP inhibition induced the greatest tumor growth delay and the highest survival. We found that PARP inhibition increases radiosensitization independent of BRCA1 status for both protons and photons. The combination of protons and PARP inhibition was the most effective in decreasing clonogenic cell survival, increasing DNA damage, and delaying tumor growth. |
| format | Article |
| id | doaj-art-d4fcd00cb3a94f908f9964af8e2f3ce3 |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Nature Portfolio |
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| series | Scientific Reports |
| spelling | doaj-art-d4fcd00cb3a94f908f9964af8e2f3ce32024-12-29T12:17:49ZengNature PortfolioScientific Reports2045-23222024-12-0114111510.1038/s41598-024-81914-wPARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapyMariam Ben Kacem0Scott J. Bright1Emma Moran2David B. Flint3David K. J. Martinus4Broderick X. Turner5Ilsa Qureshi6Rishab Kolachina7Mandira Manandhar8Poliana C. Marinello9Simona F. Shaitelman10Gabriel O. Sawakuchi11Division of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Breast Radiation Oncology, The University of Texas MD Anderson Cancer CenterDivision of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer CenterAbstract Aggressive breast cancers often fail or acquire resistance to radiotherapy. To develop new strategies to improve the outcome of aggressive breast cancer patients, we studied how PARP inhibition radiosensitizes breast cancer models to proton therapy, which is a radiotherapy modality that generates more DNA damage in the tumor than standard radiotherapy using photons. Two human BRCA1-mutated breast cancer cell lines and their isogenic BRCA1-recovered pairs were treated with a PARP inhibitor and irradiated with photons or protons. Protons (9.9 and 3.85 keV/µm) induced higher cell kill independent of BRCA1 status. PARP inhibition amplified the cell kill effect to both photons and protons (9.9 and 3.85 keV/µm) independent of BRCA1 status. Numbers of γH2AX foci, micronuclei, and cGAS-positive micronuclei were significantly higher in BRCA1-mutated cells. Cell cycle distribution and stress-induced senescence were not affected by PARP inhibition in our cell lines. In vivo, the combination of protons (3.99 keV/µm) and PARP inhibition induced the greatest tumor growth delay and the highest survival. We found that PARP inhibition increases radiosensitization independent of BRCA1 status for both protons and photons. The combination of protons and PARP inhibition was the most effective in decreasing clonogenic cell survival, increasing DNA damage, and delaying tumor growth.https://doi.org/10.1038/s41598-024-81914-wDNA repair inhibitorPARP inhibitorRadiosensitizationProton therapyRadiobiologyRadiotherapy |
| spellingShingle | Mariam Ben Kacem Scott J. Bright Emma Moran David B. Flint David K. J. Martinus Broderick X. Turner Ilsa Qureshi Rishab Kolachina Mandira Manandhar Poliana C. Marinello Simona F. Shaitelman Gabriel O. Sawakuchi PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy Scientific Reports DNA repair inhibitor PARP inhibitor Radiosensitization Proton therapy Radiobiology Radiotherapy |
| title | PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy |
| title_full | PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy |
| title_fullStr | PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy |
| title_full_unstemmed | PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy |
| title_short | PARP inhibition radiosensitizes BRCA1 wildtype and mutated breast cancer to proton therapy |
| title_sort | parp inhibition radiosensitizes brca1 wildtype and mutated breast cancer to proton therapy |
| topic | DNA repair inhibitor PARP inhibitor Radiosensitization Proton therapy Radiobiology Radiotherapy |
| url | https://doi.org/10.1038/s41598-024-81914-w |
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