PS4-05-30: Maged1 inhibition enhances sensitivity to parp inhibitors in brca-mutated breast cancer cells

Abstract Background: MAGED1 (Melanoma Antigen Gene Family, Member D1) is a member of the MAGE gene family, which is notable for its involvement in various cellular processes, including apoptosis, cell cycle regulation, and differentiation. Furthermore, previous studies showed that MAGED1 is required for double-strand breaks (DSB) repair via homologous recombination repair (HRR) and downregulation of MAGED1 sensitizes cancer cells to DNA-damaging agents. In this study, we aimed to investigate the role of MAGED1 in HRR in TNBC and BRCA1/2 mutations breast cancer. Methods: In this study, we validated MAGED1 function in HRD using siRNA in TNBC and BRCA mutant breast cancer cell lines. Cell viability was assessed by CytoFLEX after treatment with drugs (cisplatin, olaparib and niraparib) at several concentrations (0–300 µM) in Hs578T, HCC-1937 (BRCA1 5382insC), and BT-474 (BRCA2 c.0391C>A) breast cancer cell lines. Cells were transfected with control siRNA (si-Cont) or two independent siRNAs (si- MAGED1 #1, si-MAGED1 #2) targeting MAGED1. Result: Silencing of MAGED1 by siRNA in Hs578T (TNBC), HCC-1937 (BRCA1 5382insC), and BT-474 (BRCA2 c.0391C>A) cells led to enhanced sensitivity to the PARP inhibitors olaparib and niraparib, as assessed by flow cytometry using CytoFLEX. The synergistic effect between MAGED1 suppression and PARP inhibitors was more pronounced in BRCA-mutant cell lines (HCC-1937 and BT-474) compared to the TNBC Hs578T cells. In contrast, MAGED1 knockdown did not enhance sensitivity to cisplatin. Combined treatment with cisplatin and MAGED1 knockdown resulted in an unexpected increase in cell viability, warranting further investigation. To further elucidate the role of MAGED1 in HRD, additional functional studies are being conducted involving RNF8, BARD1, RAD51, and ATM. Conclusions: Our study demonstrates that silencing of MAGED1 enhances sensitivity to PARP inhibitors in BRCA1/2-mutant breast cancer cell lines. These results suggest that MAGED1 is involved in HRD and could be a therapeutic target to enhance PARP inhibitor response in breast cancer. Citation Format: L. In Hee, L. Soo Jung, K. Byeongju, L. Jeeyeon, P. Ho Yong, M. Joon Suk, L. Yangsoo, Y. Jung Dug, K. Eun Ae, J. Seolhwa, K. Jieun, C. Yee Soo. Maged1 inhibition enhances sensitivity to parp inhibitors in brca-mutated breast cancer cells [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS4-05-30.