Purpose:Resistance to adjuvant chemotherapy following enucleation continues to drive recurrence and metastasis in high-risk advanced retinoblastoma (RB), posing a major clinical challenge. To identify candidate genes, a previous transcriptomic analysis revealed markedly reduced expression of Rho GTPase-activating protein 9 (ARHGAP9) in the etoposide-resistant Y79/EDR cell line. This study aims to further investigate the effect of ARHGAP9 on chemoresistance in high-risk advanced RB. Methods:Whole-exome sequencing and reduced-representation bisulfite sequencing profiles of eight peripheral blood samples from patients with high-risk advanced RB were analyzed to identify genes with germline genetic or epigenetic alterations associated with RB prognosis. In vitro and in vivo studies on drug responsiveness and molecular mechanisms were conducted in stable ARHGAP9-silenced and ARHGAP9-overexpressing cell lines. Results:ARHGAP9 was identified through peripheral blood-based genomic and epigenomic analyses and further validated via functional study. Functional assays demonstrated that ARHGAP9 knockdown considerably decreased sensitivity to carboplatin and etoposide, whereas its overexpression restored drug responsiveness in vitro and in vivo. Mechanistic analysis indicated that ARHGAP9 downregulation markedly enhanced Ras-related C3 botulinum toxin substrate 1 (Rac1) activity as its catalytic substrate, promoted Rac1-β-catenin interaction, and facilitated their nuclear accumulation. This process induced the formation of lymphoid enhancer-binding factor 1 (LEF1)-β-catenin complex and increased expression of downstream proteins, such as c-Myc, cyclin D1, and Bcl-2, which contribute to chemotherapy resistance in RB. Conclusions:These findings provide mechanistic insights into how ARHGAP9 modulates drug responses via the Rac1/β-catenin/LEF1 signaling axis in RB and suggest that ARHGAP9 warrants further investigation as a candidate prognostic indicator or therapeutic target for advanced high-risk RB.
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