Ben Kacem Mariam, Bright Scott J, Moran Emma, Flint David B, Martinus David K J, Turner Broderick X, Qureshi Ilsa, Kolachina Rishab, Manandhar Mandira, Marinello Poliana C, Shaitelman Simona F, Sawakuchi Gabriel O
Division of Radiation Oncology, Department of Radiation Physics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Sci Rep. 2024 Dec 28;14(1):30897. doi: 10.1038/s41598-024-81914-w.
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.
侵袭性乳腺癌通常对放射治疗无效或产生耐药性。为了开发新的策略来改善侵袭性乳腺癌患者的治疗效果，我们研究了聚（ADP-核糖）聚合酶（PARP）抑制如何使乳腺癌模型对质子治疗产生放射增敏作用，质子治疗是一种放射治疗方式，与使用光子的标准放射治疗相比，它在肿瘤中产生更多的DNA损伤。用PARP抑制剂处理两个人类BRCA1突变的乳腺癌细胞系及其同基因BRCA1恢复配对细胞系，并用光子或质子进行照射。质子（9.9和3.85 keV/µm）诱导的细胞杀伤率更高，与BRCA1状态无关。PARP抑制增强了对光子和质子（9.9和3.85 keV/µm）的细胞杀伤作用，与BRCA1状态无关。在BRCA1突变细胞中，γH2AX焦点、微核和cGAS阳性微核的数量显著更高。在我们的细胞系中，细胞周期分布和应激诱导的衰老不受PARP抑制的影响。在体内，质子（3.99 keV/µm）与PARP抑制的联合应用诱导了最大的肿瘤生长延迟和最高的生存率。我们发现，PARP抑制对质子和光子均能增强放射增敏作用，且与BRCA1状态无关。质子与PARP抑制的联合应用在降低克隆形成细胞存活率、增加DNA损伤和延迟肿瘤生长方面最为有效。
