Abstract 6817: Targeting XPO1 eliminates cancer stem-like cells and abrogate hepatic metastasis in uveal melanoma

Abstract Uveal melanoma originating from the uveal tract are a rare form of the malignancy with a biology and clinical feature distinct from its more common cutaneous counterparts. Yet, UM is the most common primary intraocular tumor in adults. Despite effective treatment in primary UM with eye-sparing radiation-based techniques or enucleation, ∼50% of UM patients ultimately develop distant metastasis, most commonly in the liver. UM patients with hepatic metastasis have dismal prognosis owing to the limited efficacy of the available treatments. It is fundamental to find new therapeutic targets and develop novel treatment approaches for metastatic UM. XPO1 (also referred as CRM1), a key member of the importin β superfamily of nuclear transport receptors, mediates nuclear export of tumor suppressors and growth factors. We found that XPO1 was highly overexpressed in UM cells and positively correlated with poor prognosis of UM. Depletion of XPO1 by shRNA or its small molecular inhibitor KPT-330 significantly inhibited growth of UM cells in vitro and in vivo. Treatment with KPT-330 markedly induced apoptosis in UM cells via reducing the protein level of Survivin. Meanwhile, silencing of XPO1 by lentiviral shRNA or incubated with KPT-330 significantly decreased the percentage of ALDH+ cells and dampened self-renewal capacity in UM cells. Targeting XPO1 by KPT-330 profoundly alleviated liver metastasis burden in liver metastasis mouse model. These results suggest XPO1 may be a potential therapeutic target for patients with metastatic UM. Citation Format: Bei Jin, Hailin Zou, Jingxuan Pan. Targeting XPO1 eliminates cancer stem-like cells and abrogate hepatic metastasis in uveal melanoma [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 6817.