Abstract 1407: Alterations of <i>EIF1AX</i> and carboplatin treatment induce non-canonical translation initiation in ovarian cancer

Abstract Ovarian cancer (OvCa) is the deadliest gynecologic malignancy with high mortality due to chemoresistance. High grade serous ovarian cancer (HGSOC) is the most common subtype of ovarian cancer. The standard of care for women with HGSOC is cytoreductive surgery and chemotherapy using carboplatin, which causes DNA damage and oxidative stress. Despite aggressive treatment strategies, most patients with high grade HGSOC relapse. We recently demonstrated that post-translational modification of ribosomal proteins affects mRNA translation and protein homeostasis in ovarian cancer cells by regulating polysome formation and stress granule assembly. In this study we aim to understand the role of errors in translation initiation in chemoresistance in ovarian cancers. Eukaryotic Initiation Factor 1A X-linked (EIF1AX) is an essential eukaryotic initiation factor (eIF) that is responsible for both scanning and recognizing the canonical start codon on mRNA transcripts: Adenosine-Uracil-Guanine (AUG). Genetic alterations in EIF1AX are frequently observed in several cancers including low grade ovarian serous carcinoma (LGSOC) and high grade ovarian serous carcinoma (HGSOC). Using luciferase reporter assays, we have observed that EIF1AX ablation and carboplatin treatment in epithelial ovarian cancer cells increases translational initiation from the non-canonical start codon Uracil-Uracil-Guanine (UUG). We have also observed that EIF1AX knockdown specifically decreases the growth of carboplatin-resistant ovarian cancer cells, whereas depletion of EIF1AX enhances the growth of carboplatin-sensitive ovarian cancer cells. Moreover, EIF1AX knockdown sensitizes ovarian cancer cells to carboplatin treatment. Collectively, our results suggest that EIF1AX ablation and carboplatin treatment result in increased non-canonical translation and play a role in chemoresponses in ovarian cancers. Citation Format: Jermaine Austin, Subin Myoong, Natalia Badnarek, Sridevi Challa. Alterations of EIF1AX and carboplatin treatment induce non-canonical translation initiation in ovarian cancer [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 1407.