Abstract Background Atypical teratoid rhabdoid tumor (ATRT) is an aggressive central nervous system tumor that mostly affects children under age 3. Current intensive, multimodal therapy results in profound treatment-related toxicities. Thus, 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. Methods We harnessed an integrative approach utilizing in vitro ATRT models, drug assays, functional genomics, 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 revealed that XPO1 is highly expressed in ATRT. We utilized CRISPR-Cas9 to knockout XPO1 expression in a panel of patient-derived ATRT cells and found significant defects in cell viability and neurosphere formation. Pharmacologic inhibition of XPO1 using six different selective inhibitors of nuclear export (SINEs) across multiple ATRT cell lines showed sub-10 nM IC50 values. XPO1 inhibition led to on target degradation of XPO1 protein levels. Moreover, ATRT cells treated with selinexor showed increased apoptosis by Annexin V flow cytometry and also demonstrated G1 cell cycle arrest. Transcriptomic analysis of ATRT cells with genetic and pharmacologic inhibition of XPO1 showed significant depletion of cell cycle gene sets, with concurrent upregulation of apoptosis and TP53 signaling pathways. Lastly, using in vivo intracranial xenograft models, the combination of selinexor, radiation, and cyclophosphamide led to a reduction of ATRT tumor size and significant increase in animal survival. Conclusion We demonstrate that XPO1 is a therapeutic vulnerability in ATRT, and targeting XPO1 in combination with cytotoxic chemotherapy demonstrates high translational potential.
House et al. (Tue,) studied this question.