Evidence map›Paper›PMID 40591591›Full record

ArticleProceedings of the National Academy of Sciences of the United States of America2025

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

Jiawei Guo, Ke Li, Yue Ming, Yitong Pan, Shuangyan Tan, Hulin Ma, Shuang Chen, Yingying Duan, Yong Peng

Abstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Proceedings of the National Academy of Sciences of the United States of America, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 7 papers.

0numbers the graph read from it
0cells of the map it votes in
7citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

7 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
  4. Review
  5. Article
  6. Article
  7. A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in TNBC.Proceedings of the National Academy of Sciences of the United States of America · 2025
    Article
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

9 authors.

Jiawei GuoCenter 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.ORCID 0000-0001-5180-3514
Ke LiCenter 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.ORCID 0000-0002-8571-7128
Yue MingCenter 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.
Yitong PanCenter 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.
Shuangyan TanCenter 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.ORCID 0009-0006-2927-7558
Hulin MaCenter 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.
Shuang ChenCenter 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.ORCID 0000-0003-3263-4465
Yingying DuanCenter 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.ORCID 0009-0004-7259-1767
Yong PengCenter 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.ORCID 0000-0002-1181-3467

Funding

1.3.5 Project for Disciplines of Excellence, West China Hospital, Sichuan University ZYGD23027National Natural Science Foundation of China 82102982National Natural Science Foundation of China U24A20721Science and Technology Foundation of Sichuan Province, China 2022NSFSC1296the Fundamental Research Funds for the Central Universities SCU2022D025
6 · The paper itself

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.

Indexed as

Drug Resistance, NeoplasmProto-Oncogene Proteins c-mycRNA-Binding ProteinsRNA, CircularTriple Negative Breast NeoplasmsAnimalsBromodomain Containing ProteinsCell Line, TumorFemaleGene Expression Regulation, NeoplasticHumansMiceProtein BiosynthesisProteinsXenograft Model Antitumor Assaysbromodomain and extra-terminal domain protein, humanBromodomain Containing ProteinsIGF2BP2 protein, humanMYC protein, humanProteinsProto-Oncogene Proteins c-mycRNA-Binding ProteinsRNA, Circularacquired drug resistanceBET inhibitorscircular RNAc-MYC translationIGF2BP2

Identifiers

PMID40591591
PMCPMC12260563

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.