{"title":"环状RNA通过拮抗igf2bp2介导的TNBC中c-MYC翻译来克服对BET抑制剂的获得性耐药。","authors":"Jiawei Guo,Ke Li,Yue Ming,Yitong Pan,Shuangyan Tan,Hulin Ma,Shuang Chen,Yingying Duan,Yong Peng","doi":"10.1073/pnas.2504320122","DOIUrl":null,"url":null,"abstract":"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.","PeriodicalId":20548,"journal":{"name":"Proceedings of the National Academy of Sciences of the United States of America","volume":"78 1","pages":"e2504320122"},"PeriodicalIF":9.1000,"publicationDate":"2025-07-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC.\",\"authors\":\"Jiawei Guo,Ke Li,Yue Ming,Yitong Pan,Shuangyan Tan,Hulin Ma,Shuang Chen,Yingying Duan,Yong Peng\",\"doi\":\"10.1073/pnas.2504320122\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"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.\",\"PeriodicalId\":20548,\"journal\":{\"name\":\"Proceedings of the National Academy of Sciences of the United States of America\",\"volume\":\"78 1\",\"pages\":\"e2504320122\"},\"PeriodicalIF\":9.1000,\"publicationDate\":\"2025-07-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Proceedings of the National Academy of Sciences of the United States of America\",\"FirstCategoryId\":\"103\",\"ListUrlMain\":\"https://doi.org/10.1073/pnas.2504320122\",\"RegionNum\":1,\"RegionCategory\":\"综合性期刊\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"MULTIDISCIPLINARY SCIENCES\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Proceedings of the National Academy of Sciences of the United States of America","FirstCategoryId":"103","ListUrlMain":"https://doi.org/10.1073/pnas.2504320122","RegionNum":1,"RegionCategory":"综合性期刊","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"MULTIDISCIPLINARY SCIENCES","Score":null,"Total":0}
A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC.
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.
期刊介绍:
The Proceedings of the National Academy of Sciences (PNAS), a peer-reviewed journal of the National Academy of Sciences (NAS), serves as an authoritative source for high-impact, original research across the biological, physical, and social sciences. With a global scope, the journal welcomes submissions from researchers worldwide, making it an inclusive platform for advancing scientific knowledge.