Topoisomerase I (TOP1) inhibitors trap TOP1 cleavage complexes resulting in DNA double-strand breaks (DSBs) during replication, which are repaired by homologous recombination (HR). Triple-negative breast cancer (TNBC) could be eligible for TOP1 inhibitors given the considerable proportion of tumors with a defect in HR-mediated repair (BRCAness). The TOP1 inhibitor irinotecan was tested in 40 patient-derived xenografts (PDXs) of TNBC. BRCAness was determined with a single-nucleotide polymorphism (SNP) assay, and expression of Schlafen family member 11 (SLFN11) and retinoblastoma transcriptional corepressor 1 (RB1) was evaluated by real-time polymerase chain reaction (RT-PCR) and immunohistochemistry analyses. In addition, the combination of irinotecan and the ataxia telangiectasia and Rad3-related protein (ATR) inhibitor VE-822 was tested in SLFN11-negative PDXs, and two clinical non-camptothecin TOP1 inhibitors (LMP400 and LMP776) were tested. Thirty-eight percent of the TNBC models responded to irinotecan. BRCAness combined with high SLFN11 expression and RB1 loss identified highly sensitive tumors, consistent with the notion that deficiencies in cell cycle checkpoints and DNA repair result in high sensitivity to TOP1 inhibitors. Treatment by the ATR inhibitor VE-822 increased sensitivity to irinotecan in SLFN11-negative PDXs and abolished irinotecan-induced phosphorylation of checkpoint kinase 1 (CHK1). LMP400 (indotecan) and LMP776 (indimitecan) showed high antitumor activity in BRCA1-mutated or BRCAness-positive PDXs. Last, low SLFN11 expression was associated with poor survival in 250 patients with TNBC treated with anthracycline-based chemotherapy. In conclusion, a substantial proportion of TNBC respond to irinotecan. BRCAness, high SLFN11 expression, and RB1 loss are highly predictive of response to irinotecan and the clinical indenoisoquinoline TOP1 inhibitors.

中文翻译：

---

BRCAness、SLFN11 和 RB1 缺失可预测三阴性乳腺癌对拓扑异构酶 I 抑制剂的反应。

拓扑异构酶 I (TOP1) 抑制剂捕获 TOP1 裂解复合物，导致复制过程中的 DNA 双链断裂 (DSB)，通过同源重组 (HR) 进行修复。鉴于相当大比例的肿瘤在 HR 介导的修复 (BRCAness) 方面存在缺陷，三阴性乳腺癌 (TNBC) 可能有资格使用 TOP1 抑制剂。TOP1 抑制剂伊立替康在 40 个 TNBC 患者来源的异种移植物 (PDX) 中进行了测试。通过单核苷酸多态性 (SNP) 测定确定 BRCAness，并通过实时聚合酶链反应 (RT-PCR) 和免疫组织化学分析评估 Schlafen 家族成员 11 (SLFN11) 和视网膜母细胞瘤转录辅助抑制因子 1 (RB1) 的表达。此外，伊立替康与共济失调毛细血管扩张症和 Rad3 相关蛋白 (ATR) 抑制剂 VE-822 的组合在 SLFN11 阴性 PDX 中进行了测试，并测试了两种临床非喜树碱 TOP1 抑制剂（LMP400 和 LMP776）。38% 的 TNBC 模型对伊立替康有反应。BRCAness 与高 SLFN11 表达和 RB1 缺失相结合，鉴定出高度敏感的肿瘤，这与细胞周期检查点和 DNA 修复缺陷导致对 TOP1 抑制剂高敏感性的观点一致。ATR 抑制剂 VE-822 治疗增加了 SLFN11 阴性 PDX 对伊立替康的敏感性，并消除了伊立替康诱导的检查点激酶 1 (CHK1) 的磷酸化。LMP400 (indotecan) 和 LMP776 (indimitecan) 在 BRCA1 突变或 BRCAness 阳性 PDX 中显示出高抗肿瘤活性。最后的，在 250 名接受蒽环类化疗的 TNBC 患者中，低 SLFN11 表达与较差的生存率相关。总之，很大一部分 TNBC 对伊立替康有反应。BRCAness、高 SLFN11 表达和 RB1 缺失高度预测对伊立替康和临床茚地诺异喹啉 TOP1 抑制剂的反应。