在肺腺癌和前列腺腺癌中，神经内分泌（NE）向小细胞肺癌（SCLC）类似的侵袭性衍生物的转化与预后差相关联。我们先前表明SCLC依赖于核转运蛋白exportin 1。在此，我们探讨了exportin 1在NE转化中的作用。我们观察到肺腺癌和前列腺腺癌转化前期中exportin 1上调。在肺腺癌和前列腺腺癌细胞系中，TP53和RB1的基因失活后，exportin 1上调，并伴随着体外对exportin 1抑制剂selinexor的增敏。exportin 1抑制阻止了在与芳香化酶抑制剂enzalutamide处理后获得NE特征的不同TP53/RB1失活的前列腺癌异种移植模型中的NE转化，以及在一例肺癌转化患者源性异种移植模型中对EGFR抑制剂osimertinib的持久响应，该患者显示出腺癌/SCLC组织学特征。在腺癌-NE转化异种移植模型中，外源性SOX2表达恢复了enzalutamide促进的NE表型，尽管在selinexor治疗下。selinexor增敏了NE转化的肺和前列腺小细胞癌异种移植模型对标准细胞毒素的敏感性。综上所述，这些数据提名exportin 1抑制作为潜在治疗靶点，以限制谱系可塑性，预防或治疗肺和前列腺腺癌的NE转化。

In lung and prostate adenocarcinomas, neuroendocrine (NE) transformation to an aggressive derivative resembling small cell lung cancer (SCLC) is associated with poor prognosis. We previously described dependency of SCLC on the nuclear transporter exportin 1. Here, we explored the role of exportin 1 in NE transformation. We observed up-regulated exportin 1 in lung and prostate pretransformation adenocarcinomas. Exportin 1 was up-regulated after genetic inactivation of TP53 and RB1 in lung and prostate adenocarcinoma cell lines, accompanied by increased sensitivity to the exportin 1 inhibitor selinexor in vitro. Exportin 1 inhibition prevented NE transformation in different TP53/RB1-inactivated prostate adenocarcinoma xenograft models that acquire NE features upon treatment with the aromatase inhibitor enzalutamide and extended response to the EGFR inhibitor osimertinib in a lung cancer transformation patient-derived xenograft (PDX) model exhibiting combined adenocarcinoma/SCLC histology. Ectopic SOX2 expression restored the enzalutamide-promoted NE phenotype on adenocarcinoma-to-NE transformation xenograft models despite selinexor treatment. Selinexor sensitized NE-transformed lung and prostate small cell carcinoma PDXs to standard cytotoxics. Together, these data nominate exportin 1 inhibition as a potential therapeutic target to constrain lineage plasticity and prevent or treat NE transformation in lung and prostate adenocarcinoma.