Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer
Abstract Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to ident...
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| Format: | Article |
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Nature Portfolio
2025-01-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-025-00800-4 |
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| author | Brock J. Sishc Janapriya Saha Elizabeth M. Alves Lianghao Ding Huiming Lu Shih-Ya Wang Katy L. Swancutt James H. Nicholson Angelica Facoetti Arnold Pompos Mario Ciocca Todd A. Aguilera Michael D. Story Anthony J. Davis |
| author_facet | Brock J. Sishc Janapriya Saha Elizabeth M. Alves Lianghao Ding Huiming Lu Shih-Ya Wang Katy L. Swancutt James H. Nicholson Angelica Facoetti Arnold Pompos Mario Ciocca Todd A. Aguilera Michael D. Story Anthony J. Davis |
| author_sort | Brock J. Sishc |
| collection | DOAJ |
| description | Abstract Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response. We utilized a panel of human PDAC cell lines with diverse genetic profiles to determine their sensitivity to CIRT compared to γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity was linked to impaired DNA double-strand break (DSB) repair, particularly in cell lines with deficiencies in the homologous recombination (HR) repair pathway and/or elevated genomic instability from replication stress. Furthermore, pretreatment with the HR inhibitor B02 significantly enhanced CIRT sensitivity in a radioresistant PDAC cell line when irradiated in the spread-out Bragg peak but not at the entry position of the beam. These findings suggest that PDAC tumors with HR pathway mutations or high replication stress are more likely to benefit from CIRT while minimizing normal tissue toxicity. |
| format | Article |
| id | doaj-art-68213fd9df02440897ee5aa1bcecd7a0 |
| institution | Kabale University |
| issn | 2397-768X |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj-art-68213fd9df02440897ee5aa1bcecd7a02025-01-19T12:08:15ZengNature Portfolionpj Precision Oncology2397-768X2025-01-019111210.1038/s41698-025-00800-4Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancerBrock J. Sishc0Janapriya Saha1Elizabeth M. Alves2Lianghao Ding3Huiming Lu4Shih-Ya Wang5Katy L. Swancutt6James H. Nicholson7Angelica Facoetti8Arnold Pompos9Mario Ciocca10Todd A. Aguilera11Michael D. Story12Anthony J. Davis13Radiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterMedical Physics Unit & Research Department, CNAO National Center for Oncological HadrontherapyRadiation Oncology, University of Texas Southwestern Medical CenterMedical Physics Unit & Research Department, CNAO National Center for Oncological HadrontherapyRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterRadiation Oncology, University of Texas Southwestern Medical CenterAbstract Pancreatic ductal adenocarcinoma (PDAC) is notably resistant to conventional chemotherapy and radiation treatment. However, clinical trials indicate that carbon ion radiotherapy (CIRT) with concurrent gemcitabine is effective for unresectable locally advanced PDAC. This study aimed to identify patient characteristics predictive of CIRT response. We utilized a panel of human PDAC cell lines with diverse genetic profiles to determine their sensitivity to CIRT compared to γ-rays, assessing relative biological effectiveness (RBE) at 10% survival, which ranged from 1.96 to 3.04. Increased radiosensitivity was linked to impaired DNA double-strand break (DSB) repair, particularly in cell lines with deficiencies in the homologous recombination (HR) repair pathway and/or elevated genomic instability from replication stress. Furthermore, pretreatment with the HR inhibitor B02 significantly enhanced CIRT sensitivity in a radioresistant PDAC cell line when irradiated in the spread-out Bragg peak but not at the entry position of the beam. These findings suggest that PDAC tumors with HR pathway mutations or high replication stress are more likely to benefit from CIRT while minimizing normal tissue toxicity.https://doi.org/10.1038/s41698-025-00800-4 |
| spellingShingle | Brock J. Sishc Janapriya Saha Elizabeth M. Alves Lianghao Ding Huiming Lu Shih-Ya Wang Katy L. Swancutt James H. Nicholson Angelica Facoetti Arnold Pompos Mario Ciocca Todd A. Aguilera Michael D. Story Anthony J. Davis Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer npj Precision Oncology |
| title | Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| title_full | Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| title_fullStr | Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| title_full_unstemmed | Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| title_short | Defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| title_sort | defective homologous recombination and genomic instability predict increased responsiveness to carbon ion radiotherapy in pancreatic cancer |
| url | https://doi.org/10.1038/s41698-025-00800-4 |
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