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.

TROP2 抗体药物偶联物 (ADC) 正在积极开发中。我们试图确定是否可以通过增加 TROP2 表达来增强 TROP2 ADC 的活性。在化生性乳腺癌 (MpBC) 中，TROP2 表达有限，下调转录因子 ZEB1 上调 E-cad 和 TROP2，从而使癌症对 TROP2 ADC sacituzumab govitecan (SG) 敏感。去甲基剂地西他滨降低 DNA 甲基转移酶表达和 TROP2 启动子甲基化，随后增加 TROP2 表达。地西他滨治疗以及 TROP2 的过度表达显着增强 SG 抗肿瘤活性。在表达 TROP2 的 SLFN11 低 BC 细胞中，地西他滨还可以增加 SLFN11（一种拓扑异构酶 1 抑制剂 (TOP1) 的生物标志物）敏感性，并且与具有 TOP1 有效负载的 SG 具有协同作用。总之，TROP2和SLFN11表达可以进行表观遗传调节，去甲基化剂地西他滨与TROP2 ADC的组合可能代表一种治疗TROP2或SLFN11低表达肿瘤的新方法。