Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center, New York, New York.
New York University School of Medicine, New York, New York.
Clin Cancer Res. 2018 Oct 15;24(20):5143-5152. doi: 10.1158/1078-0432.CCR-18-0401. Epub 2018 Jun 26.
Small cell lung cancer (SCLC) is an aggressive malignancy with a critical need for novel therapies. Our goal was to determine whether PARP inhibition could sensitize SCLC cells to ionizing radiation (IR) and if so, to determine the contribution of PARP trapping to radiosensitization. Short-term viability assays and clonogenic survival assays (CSA) were used to assess radiosensitization in 6 SCLC cell lines. Doses of veliparib and talazoparib with equivalent enzymatic inhibitory activity but differing PARP trapping activity were identified and compared in CSAs. Talazoparib, IR, and their combination were tested in three patient-derived xenograft (PDX) models. Talazoparib radiosensitized 5 of 6 SCLC cell lines in short-term viability assays and confirmed in 3 of 3 cell lines by CSAs. Concentrations of 200 nmol/L talazoparib and 1,600 nmol/L veliparib similarly inhibited PAR polymerization; however, talazoparib exhibited greater PARP trapping activity that was associated with superior radiosensitization. This observation further correlated with an increased number of double-stranded DNA breaks induced by talazoparib as compared with veliparib. Finally, a dose of 0.2 mg/kg talazoparib caused tumor growth inhibition in combination with IR but not as a single agent in 3 SCLC PDX models. PARP inhibition effectively sensitizes SCLC cell lines and PDXs to IR, and PARP trapping activity enhances this effect. PARP inhibitors, especially those with high PARP trapping activity, may provide a powerful tool to improve the efficacy of radiotherapy in SCLC. .
小细胞肺癌（SCLC）是一种侵袭性恶性肿瘤，迫切需要新的治疗方法。我们的目标是确定 PARP 抑制是否能使 SCLC 细胞对电离辐射（IR）敏感，如果是，确定 PARP 捕获对放射增敏的贡献。使用 6 种 SCLC 细胞系进行短期生存能力测定和集落形成存活测定（CSA），以评估放射增敏作用。确定并比较了具有等效酶抑制活性但不同 PARP 捕获活性的 veliparib 和 talazoparib 剂量在 CSA 中的作用。在三种患者来源的异种移植（PDX）模型中测试了 talazoparib、IR 及其组合。在短期生存能力测定中，talazoparib 增敏了 6 种 SCLC 细胞系中的 5 种，并通过 3 种细胞系中的 CSA 得到证实。200nmol/L talazoparib 和 1600nmol/L veliparib 同样抑制 PAR 聚合；然而，talazoparib 表现出更高的 PARP 捕获活性，与更好的放射增敏作用相关。这一观察结果进一步与 talazoparib 引起的双链 DNA 断裂数量增加相关，而 veliparib 则较少。最后，在 3 种 SCLC PDX 模型中，0.2mg/kg talazoparib 与 IR 联合使用可导致肿瘤生长抑制，但单独使用则无效。PARP 抑制可有效增强 SCLC 细胞系和 PDX 对 IR 的敏感性，而 PARP 捕获活性可增强这种作用。PARP 抑制剂，尤其是那些具有高 PARP 捕获活性的抑制剂，可能为提高 SCLC 放射治疗的疗效提供有力工具。
