CircRNA aptamer targets IGF2BP2 to overcome acquired BETi resistance

Abstract

Bromodomain-and-extra-terminal-domain (BET) proteins are critical epigenetic readers that recognize acetylated histones to regulate transcription activation [1]. Their crucial role in activating oncogene expression (particularly c-MYC) has positioned BET inhibitors (BETi) as promising epigenetic therapeutics for refractory malignancies, including triple-negative breast cancer (TNBC). However, the clinical efficacy of BETi has been substantially limited by the rapid emergence of drug resistance, evidenced by the termination of approximately 50% of BETi monotherapy trials for solid tumors [2]. This therapeutic challenge underscores the urgent need for innovative strategies to overcome BETi resistance. A recent breakthrough study by Guo et al. identified a circular RNA (circRNA) named BISC that overcomes acquired BETi resistance by specifically targeting the RNA-binding protein IGF2BP2 to suppress c-MYC mRNA translation [3]. These findings not only reveal a novel BETi resistance mechanism but also highlight the potential of circRNA-based therapies to address the critical challenge of drug resistance in TNBC.

Drug resistance represents a major limitation, primarily emerging through either target-specific modification (e.g. altered target expression or resistance-conferring mutations) or the compensatory activation of alternative survival pathways. This challenge is particularly pronounced for epigenetic inhibitors like BETi, where genome-wide transcriptional reprogramming can simultaneously activate both therapeutic and resistance pathways. In prostate cancer, intrinsic BETi resistance stems from ubiquitin system dysregulation, characterized by diminished SPOP-mediated degradation [4] or enhanced DUB3-mediated stabilization of BET proteins [5]. Similarly, non-small cell lung cancer (NSCLC) exhibits BETi resistance in LKB1-deficient specimens [6] or through BCL6/mTOR pathway activation following BRD3 inhibition [7]. Although c-myc functions as a primary BRD4 effector in BETi-sensitive malignancies such as TNBC [8] and acute myeloid leukemia (AML) [9], its reactivation following prolonged BETi exposure drives acquired drug resistance. Notably, Guo et al. recently identified a novel resistance mechanism in TNBC, where IGF2BP2-mediated translational control sustains c-MYC expression independent of transcriptional regulation (through β-catenin, GLI2, or MED1 activation) or protein stability [3] (Fig. 1). These findings reveal enhanced c-MYC translation as a previously underappreciated cause of epigenetic therapy resistance.

Fig. 1

Molecular mechanism of acquired BETi resistance in TNBC. A In BETi-resistant cells, decreased BISC abundance releases more IGF2BP2 to preferentially bind to c-MYC mRNA, enhancing its translation and conferring BETi resistance. B Therapeutic delivery of BISC antagonizes c-MYC mRNA to interact with IGF2BP2, thereby decreasing c-MYC levels and restoring sensitivity to BET inhibition [3]

Full size image

The investigation of circRNAs requires sophisticated approaches for distinguishing functionally relevant molecules from transcriptional noise. Since the landmark discovery of circRNA CDR1as in zebrafish neurodevelopment [10], circRNA research has progressed through distinct phases: (1) Early-stage investigations focused on examining abundance changes during pathological processes, based on the premise that dysregulation implies biological function; (2) Development of CRISPR-Cas13b-based high-throughput screening platforms [11] enables direct phenotypic assessment through targeted circRNA knockdown, representing a significant methodological advancement. However, a critical challenge persists in identifying biologically relevant circRNA targets, given that most circRNAs exert their functions through post-transcriptional regulation rather than merely serving as RBP carriers. Guo et al. addressed this through an innovative target-oriented approach: after establishing IGF2BP2’s role in BETi resistance, they conducted a RIP-seq to identify circRNAs showing differential IGF2BP2 association during resistance development [3]. By focusing on circRNAs with decreased IGF2BP2 binding in resistant cells (particularly BISC, which showed the most pronounced sensitivity-associated enrichment), and further validating its selective binding to IGF2BP2 via RNA motif analysis [3]. Thus, Guo’s target-oriented approach represents a paradigm shift in this field, prioritizing target engagement and mechanistic specificity over mere abundance change.

The remarkable success of mRNA vaccines in combating the COVID-19 pandemic has reinvigorated interest in RNA-based therapeutics, demonstrating the clinical potential of nucleic acid platforms. Beyond mRNA’s protein-coding capacity, RNA aptamers represent a promising strategy to target RBP, a class traditionally considered “undruggable” proteins. The structural elucidation of BISC’s “CAC-|9–12|-XGGX” motifs specifically engaging IGF2BP2’s KH3/KH4 domains (which exhibit low homology with IGF2BP1/3) provides a molecular blueprint for selective RBP inhibition [3], overcoming the challenge of targeted RBPs lacking conventional small-molecule binding pockets. Preclinical studies of in vitro transcribed and circularized BISC in xenograft models validate circRNA-based therapeutics as a viable approach to target functional RBPs [3]. The circRNA platform presents several key advantages for clinical translation. Unlike linear RNAs, circular architecture confers nuclease resistance while maintaining low immunogenicity, key features addressing the stability and safety limitations of RNA therapeutics [12]. Moreover, tumor-specific accumulation of intravenously delivered BISC, coupled with its synergistic effects with OTX015, suggests this circRNA-based approach could overcome therapeutic resistance while minimizing systemic toxicity [3]. Pharmacokinetic analysis revealed rapid hepatic clearance and efficient renal elimination of BISC following intravenous administration, significantly reducing off-target accumulation in healthy tissues [3]. These properties, combined with its molecular specificity for IGF2BP2, establish BISC as a promising clinical candidate that addresses two major challenges in RNA therapeutics: targeted delivery and systemic toxicity.

In summary, the groundbreaking work by Guo et al. provides a compelling paradigm for developing circRNA-based aptamers to selectively target traditionally undruggable RBPs in cancer therapeutics.

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Authors and Affiliations

1. Department of Pathology and Laboratory Medicine, University of Kansas Medical Center, 3901 Rainbow Boulevard, Kansas City, KS, 66160, USA

   Christophe Nicot

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1. Christophe NicotView author publications

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CN wrote the article.

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Correspondence to Christophe Nicot.

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The author declares that he has no competing interests.

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Nicot, C. CircRNA aptamer targets IGF2BP2 to overcome acquired BETi resistance. Mol Cancer 24, 214 (2025). https://doi.org/10.1186/s12943-025-02423-6

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• Published: 10 August 2025

• DOI: https://doi.org/10.1186/s12943-025-02423-6

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