Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer.
Predictive biomarkers for sacituzumab govitecan efficacy in Trop-2-expressing triple-negative breast cancer.
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sacituzumab govitecan 在表达 Trop-2 的三阴性乳腺癌中疗效的预测生物标志物。
DOI：
10.18632/oncotarget.27766
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发表时间：
2020-10-27
期刊：
影响因子：
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通讯作者：
Goldenberg DM
中科院分区：
文献类型：
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作者：
Cardillo TM;Rossi DL;Zalath MB;Liu D;Arrojo R;Sharkey RM;Chang CH;Goldenberg DM
Sacituzumab gov.itecan(SG)是伊立替康的拓扑异构酶I抑制活性成分SN-38的人源化抗trop-2抗体通过水解链连接而成的抗体-药物结合物。我们研究了SN-38介导的双链DNA(DsDNA)断裂的trop-2表达和同源重组修复(HRR)是否在三阴性乳腺癌(TNBC)对SG的敏感性中起作用。与trp-2低表达、SG不敏感的TNBC细胞系(MDA-MB-231)相比，在具有低和中等trop-2表达的SG敏感细胞系(分别为SK-MES-1鳞状细胞肺癌和HCC1806 TNBC)中，可以评估HRR通路的激活，RAD51的表达证明了这一点。此外，对两个转导了mda-MB-231的trop-2基因的C13和C39(分别高出4倍和25倍的trop-2)进行了治疗，以确定增加trop-2的表达是否会改善SG的疗效。SG使MDA-MB-231中RAD51的表达增加2倍，但对SK-MES-1或HCC1806无影响，导致MDA-MB-231中dsDNA断裂水平降低。SG和生理盐水对亲代MDA-MB-231荷瘤小鼠的作用相似(中位生存期分别为21d和19.5d)。然而，在携带trop-2高表达C13和C39肿瘤的小鼠中，在trop-2转基因后，SG提供了显著的生存益处，即使与伊立替康相比也是如此(C13的Mst=97d比35d，C39的Mst=81d比28d；P<；0.0007)。这些结果表明，在HRR熟练的肿瘤患者中表达高水平的trop-2，以及在HRR缺陷的肿瘤患者中表达低/中等水平的trop-2时，SG可以提供比伊立替康更好的临床益处。
Sacituzumab govitecan (SG) is an antibody-drug conjugate composed of a humanized anti-Trop-2 IgG antibody conjugated via a hydrolysable linker to SN-38, the topoisomerase I-inhibitory active component of irinotecan. We investigated whether Trop-2-expression and homologous recombination repair (HRR) of SN-38-mediated double-strand DNA (dsDNA) breaks play a role in the sensitivity of triple-negative breast cancer (TNBC) to SG. Activation of HRR pathways, as evidenced by Rad51 expression, was assessed in SG-sensitive cell lines with low and moderate Trop-2-expression (SK-MES-1 squamous cell lung carcinoma and HCC1806 TNBC, respectively), compared to a low Trop-2-expressing, less SG-sensitive TNBC cell line (MDA-MB-231). Further, two Trop-2-transfectants of MDA-MB-231, C13 and C39 (4- and 25-fold higher Trop-2, respectively), were treated in mice with SG to determine whether increasing Trop-2 expression improves SG efficacy. SG mediated >2-fold increase in Rad51 in MDA-MB-231 but had no effect in SK-MES-1 or HCC1806, resulting in lower levels of dsDNA breaks in MDA-MB-231. SG and saline produced similar effects in parental MDA-MB-231 tumor-bearing mice (median survival time (MST) = 21d and 19.5d, respectively). However, in mice bearing higher Trop-2-expressing C13 and C39 tumors after Trop-2 transfection, SG provided a significant survival benefit, even compared to irinotecan (MST = 97d vs. 35d for C13, and 81d vs. 28d for C39, respectively; P < 0.0007). These results suggest that SG could provide better clinical benefit than irinotecan in patients with HRR-proficient tumors expressing high levels of Trop-2, as well as to patients with HRR-deficient tumors expressing low/moderate levels of Trop-2.