文章：

工程化药物3′UTRMYC1-18在体内降解c-MYC-STAT5A/B-PD-L1复合物以抑制转移性三阴性乳腺癌

The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer

原文发布日期：26 July 2024

DOI: 10.3390/cancers16152663

类型: Article

开放获取: 是

英文摘要：

c-MYC is overexpressed in 70% of human cancers, including triple-negative breast cancer (TNBC), yet there is no clinically approved drug that directly targets it. Here, we engineered the mRNA-stabilizing poly U sequences within the 3′UTR of c-MYC to specifically destabilize and promote the degradation of c-MYC transcripts. Interestingly, the engineered derivative outcompetes the endogenous overexpressed c-MYC mRNA, leading to reduced c-MYC mRNA and protein levels. The iron oxide nanocages (IO-nanocages) complexed with MYC-destabilizing constructs inhibited primary and metastatic tumors in mice bearing TNBC and significantly prolonged survival by degrading the c-MYC-STAT5A/B-PD-L1 complexes that drive c-MYC-positive TNBC. Taken together, we have described a novel therapy for c-MYC-driven TNBC and uncovered c-MYC-STAT5A/B-PD-L1 interaction as the target.

摘要翻译： 

c-MYC在包括三阴性乳腺癌（TNBC）在内的70%人类癌症中过度表达，但目前尚无直接靶向该蛋白的临床获批药物。本研究通过改造c-MYC基因3′非翻译区内的mRNA稳定多聚U序列，特异性破坏c-MYC转录本稳定性并促进其降解。值得注意的是，工程化改造的转录本能够竞争性抑制内源性过表达的c-MYC mRNA，从而降低c-MYC mRNA及蛋白水平。与MYC去稳定化构建体复合的氧化铁纳米笼（IO-nanocages）通过降解驱动c-MYC阳性TNBC的c-MYC-STAT5A/B-PD-L1复合物，有效抑制TNBC荷瘤小鼠的原发性和转移性肿瘤，并显著延长生存期。综上所述，本研究不仅提出了一种针对c-MYC驱动型TNBC的新型疗法，同时揭示了c-MYC-STAT5A/B-PD-L1相互作用可作为治疗靶点。

原文链接：

The Engineered Drug 3′UTRMYC1-18 Degrades the c-MYC-STAT5A/B-PD-L1 Complex In Vivo to Inhibit Metastatic Triple-Negative Breast Cancer