Abstract 540: AVJ16 alleviates ABCB1-mediated doxorubicin chemoresistance via IGF2BP1 inhibition

Background: The efficacy of chemotherapy is often compromised by multidrug resistance (MDR), driven by the overexpression of ATP-binding Cassette Sub-family B Member 1 (ABCB1). While ABCB1 inhibitors are urgently needed, toxicity and pharmacokinetic challenges have limited clinical progress. Dysregulation of N6-Methyladenosine (m6A)—a key mRNA modification involved in gene regulation—is linked to chemoresistance, presenting a potential target to counteract ABCB1-mediated MDR. Aim: To examine m6A’s role in ABCB1-driven chemoresistance in uterine sarcoma and breast cancer and evaluate alternative ABCB1 inhibitors. Methods: RT-qPCR analysis identified Insulin-like Growth Factor 2 mRNA-binding protein 1 (IGF2BP1)—an m6A reader—as the most upregulated m6A regulator in MDR uterine sarcoma cells. Expression levels were validated in parental and MDR uterine sarcoma and breast cancer cells. GEO dataset of breast cancer patients treated with neoadjuvant chemotherapy was analyzed in silico to determine IGF2BP1-ABCB1 correlation. Functional assays were performed to evaluate IGF2BP1 knockdown and inhibition effects by AVJ16 (an IGF2BP1 inhibitor) on ABCB1 expression and doxorubicin resistance. Additionally, 3-deazaadenosine (DAA), an m6A inhibitor, was added to MDR cells with IGF2BP1 knockdown or AVJ16 treatment to confirm IGF2BP1’s role in m6A-dependent regulation of ABCB1 and chemoresistance. Results: IGF2BP1 and ABCB1 were significantly upregulated in MDR uterine sarcoma and breast cancer cells. In silico analysis confirmed a positive correlation between IGF2BP1 and ABCB1 expression, linking IGF2BP1 to ABCB1-driven chemoresistance clinically. IGF2BP1 knockdown in MDR uterine sarcoma cells reduced ABCB1 expression and doxorubicin resistance, evidenced by lower cell viability and colony formation. Moreover, AVJ16 significantly decreased doxorubicin’s half-maximal inhibitory concentration (IC50) in MDR uterine sarcoma by downregulating ABCB1 expression. DAA, combined with IGF2BP1 knockdown or AVJ16, markedly enhanced doxorubicin sensitivity, supporting IGF2BP1’s m6A-dependent role in MDR. Conclusion: IGF2BP1 is a novel m6A-dependent regulator of ABCB1-driven chemoresistance. These findings highlight AVJ16 as a promising therapeutic candidate for overcoming ABCB1-driven MDR cancers. Citation Format: Eveiyn Weng Yan Phoon, Kowit-Yu Chong. AVJ16 alleviates ABCB1-mediated doxorubicin chemoresistance via IGF2BP1 inhibition [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 540.