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

Chidiebere U Awah; Joo Sun Mun; Aloka Paragodaarachchi; Baris Boylu; Chika Ochu; Hiroshi Matsui; Olorunseun O Ogunwobi

doi:10.3390/cancers16152663

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

Cancers (Basel). 2024 Jul 26;16(15):2663. doi: 10.3390/cancers16152663.

Authors

Chidiebere U Awah^{1

2}, Joo Sun Mun³, Aloka Paragodaarachchi^{3

4}, Baris Boylu¹, Chika Ochu¹, Hiroshi Matsui^{3

5

6}, Olorunseun O Ogunwobi^{1

2

7}

Affiliations

¹ Department of Biological Sciences, Hunter College, City University of New York, New York, NY 10065, USA.
² Joan and Sanford I. Weill Department of Medicine, Weill Cornell Medicine, Cornell University, New York, NY 14850, USA.
³ Department of Chemistry, Hunter College, City University of New York, New York, NY 10065, USA.
⁴ Ph.D. Program in Chemistry, The Graduate Center, City University of New York, New York, NY 10016, USA.
⁵ Ph.D. Program in Biochemistry, The Graduate Center, City University of New York, New York, NY 10016, USA.
⁶ Department of Biochemistry, Weill Cornell Medicine, Cornell University, New York, NY 14850, USA.
⁷ Hunter College for Cancer Health Disparities Research, Hunter College, City University of New York, New York, NY 10065, USA.

Abstract

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.

Keywords: c-MYC-STAT5A/5B-PD-L1 complex; destabilized 3′UTR (AU-rich elements); iron oxide nanocage (IO); mRNA poly U stabilizing elements; nonsense-mediated decay (NMD); triple-negative breast cancer (TNBC).

Abstract

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