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A circular RNA overcomes acquired resistance to BET inhibitors by antagonizing IGF2BP2-mediated c-MYC translation in triple-negative breast cancer

ABSTRACT: The bromodomain and extra-terminal domain (BET) proteins are promising therapeutic targets to treat refractory solid tumors including triple-negative breast cancer (TNBC); however, acquired resistance remains a major challenge in the clinic. Therefore, elucidation on the mechanism underlying acquired drug resistance is of practical significance. In this study, we found that abnormally upregulated RNA-binding protein IGF2BP2 acts as crucial contributor to triggering acquired BETi resistance in TNBC by facilitating the translational process of c-myc mRNAs. Considering that IGF2BP2 itself are not ideal drug target for small-molecular compounds, we carried out an RIP-seq experiment and identified circRNA-BISC as a potent IGF2BP2 repressor, which was able to repress both c-MYC translation process and acquired BETi resistance. BISC possesses a typical ‘CAC-linker-XGGX’ motif to specifically bind with IGF2BP2 without interactions with IGF2BP1 and IGF2BP3. The effectiveness and specificity of BISC on IGF2BP2 prompted further evaluation of the BISC-based RNA therapeutics in TNBC. In vitro transcribed and circularized BISC, when combined with OTX-015, achieves impressive tumor remission of the BETi-resistant TNBCs without obvious toxicities. Collectively, our result support BISC as a potent IGF2BP2 repressor and highlight the feasibility of pursuing BISC restoration by circRNA therapeutics to overcome BETi resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290133 | GEO | 2025/03/01

REPOSITORIES: GEO

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