Abstract Background: Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that mostly affects infants and children under the age of 3. While there have been some improvements in clinical outcomes with multimodal therapy, there remains significant morbidity and toxicities associated with intensive therapy. Therefore, there is a dire need for less toxic and improved therapies for children with ATRT. The identification of cancer dependencies can be utilized to determine novel therapeutic approaches. We identified exportin-1 (XPO1), a nuclear export protein that transports cargo proteins from the nucleus to the cytoplasm, as a novel dependency in ATRT. In other cancers, elevated XPO1 expression has been associated with poor prognosis. Methods: We utilized an integrative approach harnessing in vitro ATRT models, functional genomics, drug assays, flow cytometry, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a therapeutic vulnerability in ATRT. Results: RNA-sequencing data across pediatric brain tumor cell lines reveals that XPO1 is highly expressed in ATRT cells. We utilized CRIPSR-Cas9 to knockout XPO1 expression in a panel of patient-derived ATRT cells and found significant defects in cell viability and proliferation. Pharmacologic inhibition of XPO1 using six different selective inhibitors of nuclear export (SINEs) in multiple ATRT cell lines showed sub-10 nM IC50 values. We found that XPO1 inhibition led to on target degradation of XPO1 protein levels. In ATRT cells treated with an XPO1 inhibitor selinexor, Annexin V flow cytometry showed increased apoptosis relative to DMSO. In addition, ATRT cells treated with selinexor demonstrated G1 cell cycle arrest. Western blotting revealed a significant increase in cleaved caspase-3 levels and activation of TP53 with pharmacologic XPO1 inhibition. Transcriptomic analysis of ATRT cells with genetic and pharmacologic inhibition of XPO1 showed significant upregulation of apoptosis and TP53 signaling pathways, with concurrent depletion of cell cycle gene sets. Lastly, using in vivo intracranial xenograft models, the combination of selinexor with radiation and cyclophosphamide led to a reduction of tumor size and significant increase in animal survival. Conclusion: We demonstrate that XPO1 is a dependency in ATRT, and targeting XPO1 in combination with cytotoxic chemotherapy shows high translational potential. Citation Format: Tessa O. House, Irina Alimova, Shawna Larsen, Gillian Murdock, Angela Pierce, Breauna Brunt, Stefania Tocci, Sofia Krykunenko, Marissa Coppola, Anat Erdreich-Epstein, Ron Firestein, Natalie Serkova, Rajeev Vibhakar, Jessica W. Tsai. XPO1 as a therapeutic vulnerability in atypical teratoid rhabdoid tumors abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 3487.
House et al. (Fri,) studied this question.