Awah Chidiebere U, Mun Joo Sun, Paragodaarachchi Aloka, Boylu Baris, Ochu Chika, Matsui Hiroshi, Ogunwobi Olorunseun O
Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA.
Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 14850, USA.
Cancers (Basel). 2024 Jul 26;16(15):2663. doi: 10.3390/cancers16152663.
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.
c-MYC在包括三阴性乳腺癌（TNBC）在内的70%的人类癌症中过表达，但目前尚无临床批准的直接靶向它的药物。在此，我们在c-MYC的3'UTR内设计了mRNA稳定的聚U序列，以特异性地使c-MYC转录本不稳定并促进其降解。有趣的是，工程衍生物胜过内源性过表达的c-MYC mRNA，导致c-MYC mRNA和蛋白质水平降低。与MYC稳定构建体复合的氧化铁纳米笼（IO-纳米笼）抑制了携带TNBC的小鼠的原发性和转移性肿瘤，并通过降解驱动c-MYC阳性TNBC的c-MYC-STAT5A/B-PD-L1复合物显著延长了生存期。综上所述，我们描述了一种针对c-MYC驱动的TNBC的新疗法，并揭示了c-MYC-STAT5A/B-PD-L1相互作用作为靶点。
