Exportin-1 is a therapeutic vulnerability in atypical teratoid/rhabdoid tumors

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 pharmacologic XPO1 inhibitors. Consistently, our transcriptomic data revealed upregulation of apoptosis and TP53 signaling pathways, and concomitant depletion of cell cycle gene sets.

In vivo, selinexor in combination with radiation and cyclophosphamide significant reduction in tumor volume and increased animal survival in intracranial ATRT xenograft models. Together, our data reveals XPO1 as a novel genetic dependency and potent therapeutic target in ATRT.