Comp34 displays potent preclinical antitumor efficacy in triple-negative breast cancer via inhibition of NUDT3-AS4, a novel oncogenic long noncoding RNA

Qiongyu Hao,Magda Shaheen,Qiao-Hong Chen,Qing Geng,Pranabananda Dutta,Yahya Elshimali,Seyung Chung,Katrina Schrode,Wei Cao,Jay Vadgama,Wenhong Deng,Yong Wu,Qun Li,Guanglin Chen,Donghui Zhu,Jieqing Li,Ke Wu,Piwen Wang,Kun Wang

doi:10.1038/s41419-020-03235-w

Abstract

The abnormal PI3K/AKT/mTOR pathway is one of the most common genomic abnormalities in breast cancers including triple-negative breast cancer (TNBC), and pharmacologic inhibition of these aberrations has shown activity in TNBC patients. Here, we designed and identified a small-molecule Comp34 that suppresses both AKT and mTOR protein expression and exhibits robust cytotoxicity towards TNBC cells but not nontumorigenic normal breast epithelial cells. Mechanically, long noncoding RNA (lncRNA) AL354740.1-204 (also named as NUDT3-AS4) acts as a microRNA sponge to compete with AKT1/mTOR mRNAs for binding to miR-99s, leading to decrease in degradation of AKT1/mTOR mRNAs and subsequent increase in AKT1/mTOR protein expression. Inhibition of lncRNA-NUDT3-AS4 and suppression of the NUDT3-AS4/miR-99s association contribute to Comp34-affected biologic pathways. In addition, Comp34 alone is effective in cells with secondary resistance to rapamycin, the best-known inhibitor of mTOR, and displays a greater in vivo antitumor efficacy and lower toxicity than rapamycin in TNBC xenografted models. In conclusion, NUDT3-AS4 may play a proproliferative role in TNBC and be considered a relevant therapeutic target, and Comp34 presents promising activity as a single agent to inhibit TNBC through regulation of NUDT3-AS4 and miR-99s.

Highlights

Triple-negative breast cancers (TNBCs) account for20% of all breast cancers (BCs) and are associated with adverse clinical outcomes[1]
We focus on studying the anti-TNBC effect and the related molecular mechanism of Comp[34] in the following work
To substantiate the action mechanism of Comp[34], we demonstrated that Comp[34] reduces and NUDT3-AS4 increases the luciferase activity in WT AKT1 and mTOR

Summary

Introduction

20% of all breast cancers (BCs) and are associated with adverse clinical outcomes[1]. AKT/mTOR pathway was considered to be an effective strategy for the treatment of TNBC recently. CeRNA acts as a molecular sponge of microRNAs through its miRNA response elements (MRE), inhibiting the expression of miRNA target genes. Recent studies on solid tumors and hematopoietic malignancies reveal that ceRNAs plays an important role in the pathogenesis of tumors through changing. Official journal of the Cell Death Differentiation Association. Identification of the characteristics, functions and mechanisms of ceRNAs will further deepen our basic understanding of the pathogenesis of RNA-mediated cancer, but may provide clues for the development of novel RNA-based therapeutic strategies for cancer

Methods

Results

Conclusion