Sishc Brock J, Saha Janapriya, Alves Elizabeth M, Ding Lianghao, Lu Huiming, Wang Shih-Ya, Swancutt Katy L, Nicholson James H, Facoetti Angelica, Pompos Arnold, Ciocca Mario, Aguilera Todd A, Story Michael D, Davis Anthony J
Radiation Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.
Mayo Clinic Florida, Jacksonville, FL, USA.
NPJ Precis Oncol. 2025 Jan 17;9(1):20. doi: 10.1038/s41698-025-00800-4.
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.
胰腺导管腺癌（PDAC）对传统化疗和放射治疗具有显著抗性。然而，临床试验表明，碳离子放疗（CIRT）联合吉西他滨对无法切除的局部晚期PDAC有效。本研究旨在确定预测CIRT反应的患者特征。我们使用了一组具有不同基因谱的人PDAC细胞系，以确定它们与γ射线相比对CIRT的敏感性，评估10%存活率时的相对生物效应（RBE），其范围为1.96至3.04。放射敏感性增加与DNA双链断裂（DSB）修复受损有关，特别是在同源重组（HR）修复途径存在缺陷和/或复制应激导致基因组不稳定性升高的细胞系中。此外，当在扩展布拉格峰处照射时，用HR抑制剂B02预处理可显著增强耐放射性PDAC细胞系对CIRT的敏感性，但在束流进入位置照射时则不然。这些发现表明，具有HR途径突变或高复制应激的PDAC肿瘤更有可能从CIRT中获益，同时将正常组织毒性降至最低。
