A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC

• 成果类型: Article
• 署名作者: Guo, Jiawei; Li, Ke; Ming, Yue; Pan, Yitong; Tan, Shuangyan; Ma, Hulin; Chen, Shuang; Duan, Yingying; Peng, Yong
• 署名单位: Sichuan University; Sichuan University; Tianfu Jincheng Laboratory
• 刊物名称: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• ISSN/ISSBN: 0027-8719
• DOI: 10.1073/pnas.2504320122
• 发表日期: 2025-07-01
• 关键词: messenger-rna; binding protein; bromodomain inhibition; cancer; STABILITY; efficacy; target

摘要

Bromodomain-and-extraterminal-domain (BET) proteins are promising therapeutic targets for refractory solid tumors, including triple-negative breast cancer (TNBC). However, acquired resistance to BET inhibitors (BETi) remains a significant clinical challenge. Elucidation of the underlying mechanisms of BETi resistance is therefore of critical importance. In this study, we identified the RNA-binding protein IGF2BP2 as a key driver of acquired BETi resistance in TNBC, primarily through its role in enhancing the translation of c-MYC mRNA. Given that IGF2BP2 is not an ideal target for small-molecular drugs, we performed RNA immunoprecipitation sequencing (RIP-Seq) and found circRNA-BISC as a potent IGF2BP2 repressor. BISC effectively inhibited both c-MYC translation and BETi resistance. Notably, BISC contains a CAC-linker-XGGX motif that specifically binds IGF2BP2 rather than to IGF2BP1 and IGF2BP3. The efficacy and selectivity of BISC in targeting IGF2BP2 prompted further exploration of BISC-based RNA therapeutics for TNBC. In vitro transcribed and circularized BISC, when combined with the BETi OTX-015, demonstrated impressive tumor regression in BETi-resistant TNBC models without detectable toxicity. These findings establish BISC as a potent IGF2BP2 repressor and highlight the feasibility of circRNA-based therapeutic strategies to overcome BETi resistance in TNBC.