Coussy Florence, El-Botty Rania, Château-Joubert Sophie, Dahmani Ahmed, Montaudon Elodie, Leboucher Sophie, Morisset Ludivine, Painsec Pierre, Sourd Laura, Huguet Léa, Nemati Fariba, Servely Jean-Luc, Larcher Thibaut, Vacher Sophie, Briaux Adrien, Reyes Cécile, La Rosa Philippe, Lucotte Georges, Popova Tatiana, Foidart Pierre, Sounni Nor Eddine, Noel Agnès, Decaudin Didier, Fuhrmann Laetitia, Salomon Anne, Reyal Fabien, Mueller Christopher, Ter Brugge Petra, Jonkers Jos, Poupon Marie-France, Stern Marc-Henri, Bièche Ivan, Pommier Yves, Marangoni Elisabetta
Translational Research Department, Institut Curie, PSL Research University, 75005 Paris, France.
Medical Oncology Department, Institut Curie, PSL Research University, 75005 Paris, France.
Sci Transl Med. 2020 Feb 19;12(531). doi: 10.1126/scitranslmed.aax2625.
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.
拓扑异构酶I（TOP1）抑制剂会捕获TOP1切割复合物，在复制过程中导致DNA双链断裂（DSB），这些双链断裂由同源重组（HR）修复。鉴于相当一部分肿瘤存在HR介导修复缺陷（BRCAness），三阴性乳腺癌（TNBC）可能适合使用TOP1抑制剂。在40个TNBC患者来源的异种移植瘤（PDX）中对TOP1抑制剂伊立替康进行了测试。通过单核苷酸多态性（SNP）检测确定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施拉芬家族成员11（SLFN11）和视网膜母细胞瘤转录共抑制因子1（RB1）的表达。此外，在SLFN11阴性的PDX中测试了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-82（2）的联合用药情况，并测试了两种临床非喜树碱类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缺失相结合可识别出高度敏感的肿瘤，这与细胞周期检查点和DNA修复缺陷导致对TOP1抑制剂高度敏感的观点一致。ATR抑制剂VE-822治疗可增加SLFN11阴性PDX对伊立替康的敏感性，并消除伊立替康诱导的检查点激酶1（CHK1）磷酸化。LMP400（茚并替康）和LMP776（茚地卡星）在BRCA1突变或BRCAness阳性的PDX中显示出高抗肿瘤活性。最后，在250例接受蒽环类化疗的TNBC患者中，低SLFN11表达与较差的生存率相关。总之，相当一部分TNBC对伊立替康有反应。BRCAness、高SLFN11表达和RB1缺失对伊立替康和临床茚并异喹啉类TOP1抑制剂的反应具有高度预测性。
