التفاصيل البيبلوغرافية
| العنوان: |
Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers. |
| المؤلفون: |
Quintanal-Villalonga, Alvaro, Durani, Vidushi, Sabet, Amin, Redin, Esther, Kawasaki, Kenta, Shafer, Moniquetta, Karthaus, Wouter R., Zaidi, Samir, Zhan, Yingqian A., Manoj, Parvathy, Sridhar, Harsha, Shah, Nisargbhai S., Chow, Andrew, Bhanot, Umesh K., Linkov, Irina, Asher, Marina, Yu, Helena A., Qiu, Juan, de Stanchina, Elisa, Patel, Radhika A. |
| المصدر: |
Science Translational Medicine; 8/2/2023, Vol. 15 Issue 707, p1-14, 14p |
| مصطلحات موضوعية: |
LUNG cancer, SMALL cell lung cancer, PROSTATE cancer, ANDROGEN receptors, SMALL cell carcinoma, PHENOTYPIC plasticity, ANDROGEN drugs |
| مستخلص: |
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. Editor's summary: Lung and prostate adenocarcinomas can undergo neuroendocrine (NE) transformation, which results in a more aggressive tumor and worst prognosis for patients. Here, Quintanal-Villalonga et al. explored the role of exportin 1 in this NE transformation and saw that it was elevated after inactivation of TP53 and RB1. This increase resulted in an increased sensitivity to an exportin 1 inhibitor, selinexor, which additionally sensitized NE-transformed mouse models to standard chemotherapy. This suggests exportin 1 as a potential therapeutic target to both prevent and treat NE-transformed lung and prostate adenocarcinomas that requires further study. —Dorothy Hallberg [ABSTRACT FROM AUTHOR] |
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| قاعدة البيانات: |
Complementary Index |
