Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer
Targeted radiosensitization with PARP1 inhibition: optimization of therapy and identification of biomarkers of response in breast cancer
复制标题
DOI：
10.1007/s10549-014-3085-5
复制
发表时间：
2014-08-01
影响因子：
3.8
通讯作者：
Pierce, Lori J.
中科院分区：
文献类型：
--
作者：
Feng, Felix Y.;Speers, Corey;Pierce, Lori J.
对于某些患者来说，乳腺癌的持续局部控制是一个重要问题。抑制 PARP1 是一种有前途的放射增敏 (RS) 策略。我们试图通过建立最有效的治疗方案、PARP1 介导的 RS 程度来优化 PARP1 抑制和放射 (RT) 治疗，并确定预测乳腺癌模型疗效的早期生物标志物。使用克隆生存测定，我们评估了乳腺癌细胞系中 PARP1 抑制诱导的内在放射敏感性和 RS。使用蛋白质印迹、流式细胞术和免疫荧光评估潜在的反应生物标志物，并使用肿瘤异种移植实验进行体内验证。在一组 BC 和正常乳腺上皮细胞系中，PARP1 抑制剂 ABT-888 优先对乳腺癌（相对于正常）细胞进行放射增敏，增强比 (EnhR) 高达 2.3，与固有 BC 亚型或 BRCA 突变状态无关。并行治疗和辅助治疗导致所有测试方案中 EnhR 最高。 RS 程度与 PARP1 活性、DNA 损伤/修复或细胞周期分布的预处理标记无关。 RT 后 24 小时 PARP1 活性的增加与联合治疗后的敏感性相关。研究结果在乳腺癌异种移植模型中得到证实。我们的研究表明，PARP1 抑制可提高 RT 的治疗指数，与 BC 亚型或 BRCA1 突变状态无关，并且 PARP1 活性可作为临床相关的反应生物标志物。这些研究促成了一项临床试验 (TBCRC024)，该试验纳入了乳腺癌患者中 PARP1 抑制剂和 RT 的治疗内生物标志物分析。
Sustained locoregional control of breast cancer is a significant issue for certain patients. Inhibition of PARP1 is a promising strategy for radiosensitization (RS). We sought to optimize therapy with PARP1 inhibition and radiation (RT) by establishing the most effective treatment schedule, degree of PARP1-mediated RS, and identify early biomarkers predictive of efficacy in breast cancer models. Using clonogenic survival assays, we assessed intrinsic radiosensitivity and RS induced by PARP1 inhibition in breast cancer cell lines. Potential biomarkers of response were evaluated using western blotting, flow cytometry, and immunofluorescence with validation in vivo using tumor xenograft experiments. Across a panel of BC and normal breast epithelial cell lines, the PARP1 inhibitor ABT-888 preferentially radiosensitizes breast cancer (vs. normal) cells with enhancement ratios (EnhR) up to 2.3 independent of intrinsic BC subtype or BRCA mutational status. Concurrent and adjuvant therapy resulted in the highest EnhR of all schedules tested. The degree of RS did not correlate with pretreatment markers of PARP1 activity, DNA damage/repair, or cell cycle distribution. Increases in PARP1 activity 24 h after RT were associated with sensitivity after combination treatment. Findings were confirmed in breast cancer xenograft models. Our study demonstrates that PARP1 inhibition improves the therapeutic index of RT independent of BC subtype or BRCA1 mutational status and that PARP1 activity may serve as a clinically relevant biomarker of response. These studies have led to a clinical trial (TBCRC024) incorporating intratreatment biomarker analyses of PARP1 inhibitors and RT in breast cancer patients.