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Retinoids in Leukemia and Cellular Processes / Chromatin Remodeling and Cancer · Journal article
Neuro-oncology Advances · August 8, 2026
Encouraging direction, but not yet definitive.
This preclinical study demonstrates that XPO1 is a genetic dependency in patient-derived ATRT cell lines and that the XPO1 inhibitor selinexor activates TP53 pathways, reduces cell viability, and improves survival in intracranial xenograft models when combined with radiation and cyclophosphamide. The findings are mechanistically coherent and biologically plausible but remain in the preclinical domain; clinical translation and human efficacy are not yet established.
Preclinical integrated study: patient-derived cell lines, CRISPR/Cas9 functional genomics, pharmacologic inhibition, transcriptomics, and intracranial xenograft models. Patient-derived ATRT cell lines compared to other pediatric brain tumor cell lines; intracranial xenograft models. Intervention: XPO1 inhibition: CRISPR/Cas9 knockdown; six selective nuclear export inhibitors (SINEs) including selinexor; in vivo: selinexor combined with radiation and cyclophosphamide. Compared with: Untreated or vehicle control for cell viability and apoptosis assays; standard therapies mentioned as context but not formally compared in this study.
High XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines identified by RNA-sequencing CRISPR/Cas9 knockdown and six selective nuclear export inhibitors (SINEs) led to significant reduction in cell viability and proliferation in patient-derived ATRT cells Selinexor treatment increased apoptosis, induced G0 phase cell cycle arrest, and upregulated TP53 signaling pathways in ATRT cells
Preclinical model; human clinical efficacy and safety not yet demonstrated
These preclinical findings identify XPO1 as a rational therapeutic target in ATRT and support evaluation of selinexor-based combination therapy in clinical trials. However, clinicians should await human efficacy data before considering this a therapeutic option.
Sound preclinical study with patient-derived models and in vivo validation showing XPO1 inhibition activates TP53 and reduces tumor burden, but lacks clinical trial data and human efficacy evidence.
As stated by the source record.
Quoted from the source exactly as published.
These preclinical findings identify XPO1 as a rational therapeutic target in ATRT and support evaluation of selinexor-based combination therapy in clinical trials. However, clinicians should await human efficacy data before considering this a therapeutic option.
Graded across the dimensions that decide whether you should act, each from what the source actually supports. There is no single score, and where a dimension was not assessed it says so.
Abstract Background Atypical teratoid/rhabdoid tumor (ATRT) is an aggressive central nervous system tumor mostly affecting young children. Improved and less toxic therapies for children with ATRT are imperative due to the toxicities associated with current treatments. Furthermore, existing therapies do not address the underlying genetic drivers of ATRT. In this study, we sought to determine whether exportin-1 (XPO1) is a genetic dependency and therapeutic target in ATRT. Methods We utilized an integrative approach harnessing patient-derived ATRT cell lines, functional genomics, pharmacologic assays, transcriptomics, and in vivo intracranial xenograft models to systematically test the hypothesis that XPO1 is a novel dependency in ATRT. Results Analysis of RNA-sequencing datasets revealed high XPO1 expression in ATRT cells compared to other pediatric brain tumor cell lines. Both CRISPR/Cas9 genetic knockdown and pharmacologic inhibition of XPO1 using six selective inhibitors of nuclear export (SINEs) in patient-derived ATRT cells led to significant reduction in cell viability and proliferation. Furthermore, we observed increased apoptosis, G0 phase cell cycle arrest, and upregulation of TP53 signaling pathways in cells treated with the SINE selinexor. Consistently, our transcriptomic data revealed the upregulation of apoptosis and TP53 signaling pathways and concomitant depletion of cell cycle gene sets. In vivo, selinexor in combination with radiation and cyclophosphamide led to significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. Conclusions Our data reveal XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.
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