Guo Jiawei, Li Ke, Ming Yue, Pan Yitong, Tan Shuangyan, Ma Hulin, Chen Shuang, Duan Yingying, Peng Yong
Center for Molecular Oncology, Frontiers Science Center for Disease-related Molecular Network, State Key Laboratory of Biotherapy and Cancer Center, State Key Laboratory of Respiratory Health and Multimorbidity, West China Hospital, Sichuan University, Chengdu 610041, China.
Tianfu Jincheng Laboratory, Chengdu 610212, China.
Proc Natl Acad Sci U S A. 2025 Jul 8;122(27):e2504320122. doi: 10.1073/pnas.2504320122. Epub 2025 Jul 1.
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.
溴结构域和额外末端结构域（BET）蛋白是难治性实体瘤（包括三阴性乳腺癌（TNBC））有前景的治疗靶点。然而，对BET抑制剂（BETi）获得性耐药仍然是一个重大的临床挑战。因此，阐明BETi耐药的潜在机制至关重要。在本研究中，我们确定RNA结合蛋白IGF2BP2是TNBC中获得性BETi耐药的关键驱动因素，主要是通过其增强c-MYC mRNA翻译的作用。鉴于IGF2BP2不是小分子药物的理想靶点，我们进行了RNA免疫沉淀测序（RIP-Seq），发现circRNA-BISC是一种有效的IGF2BP2抑制剂。BISC有效抑制c-MYC翻译和BETi耐药。值得注意的是，BISC包含一个“CAC-连接子-XGGX”基序，该基序特异性结合IGF2BP2，而不与IGF2BP1和IGF2BP3结合。BISC靶向IGF2BP2的有效性和选择性促使人们进一步探索基于BISC的TNBC RNA疗法。体外转录和环化的BISC与BETi OTX-015联合使用时，在BETi耐药的TNBC模型中显示出令人印象深刻的肿瘤消退，且未检测到毒性。这些发现确立了BISC作为一种有效的IGF2BP2抑制剂，并突出了基于circRNA的治疗策略克服TNBC中BETi耐药的可行性。
