通过表观遗传学上调TROP2和SLFN11可以增强TROP2抗体药物结合物sacitizumab govitecan的治疗效果。
Epigenetically upregulating TROP2 and SLFN11 enhances therapeutic efficacy of TROP2 antibody drug conjugate sacitizumab govitecan.
发表日期：2023 Aug 11
作者：
Ming Zhao, Timothy P DiPeri, Maria Gabriela Raso, Xiaofeng Zheng, Yasmeen Qamar Rizvi, Kurt W Evans, Fei Yang, Argun Akcakanat, Marco Roberto Estecio, Debu Tripathy, Ecaterina E Dumbrava, Senthil Damodaran, Funda Meric-Bernstam
来源：
npj Breast Cancer
摘要：
TROP2抗体药物联合物（ADCs）正在积极开发中。我们试图确定是否可以通过增加TROP2的表达来增强TROP2 ADCs的活性。在转化隔离性乳腺癌（MpBC）中，TROP2的表达有限，并且下调转录因子ZEB1可以上调E-cad和TROP2，从而增加癌细胞对TROP2 ADC sacituzumab govitecan（SG）的敏感性。去甲基化剂去甲基化剂可以降低DNA甲基转移酶的表达和TROP2启动子的甲基化，从而增加TROP2的表达。去甲基化剂治疗以及TROP2的过表达显著增强了SG的抗肿瘤活性。去甲基化剂还可以增加SLFN11的表达，SLFN11是拓扑异构酶1抑制剂（TOP1）敏感性的生物标志物，并且在TROP2表达的SLFN11低BC细胞中，与SG（具有TOP1荷载）具有协同作用。总之，TROP2和SLFN11的表达可以通过上遗传调控，并且去甲基化剂去甲基化剂与TROP2 ADCs的联合可能代表了一种针对低TROP2或SLFN11表达的肿瘤的新型治疗方法。© 2023. Springer Nature Limited.
TROP2 antibody drug conjugates (ADCs) are under active development. We seek to determine whether we can enhance activity of TROP2 ADCs by increasing TROP2 expression. In metaplastic breast cancers (MpBC), there is limited expression of TROP2, and downregulating transcription factor ZEB1 upregulates E-cad and TROP2, thus sensitizing cancers to TROP2 ADC sacituzumab govitecan (SG). Demethylating agent decitabine decreases DNA methyltransferase expression and TROP2 promoter methylation and subsequently increases TROP2 expression. Decitabine treatment as well as overexpression of TROP2 significantly enhance SG antitumor activity. Decitabine also increases SLFN11, a biomarker of topoisomerase 1 inhibitor (TOP1) sensitivity and is synergistic with SG which has a TOP1 payload, in TROP2-expressing SLFN11-low BC cells. In conclusion, TROP2 and SLFN11 expression can be epigenetically modulated and the combination of demethylating agent decitabine with TROP2 ADCs may represent a novel therapeutic approach for tumors with low TROP2 or SLFN11 expression.© 2023. Springer Nature Limited.