Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers Journal Article


Authors: Quintanal-Villalonga, A.; Durani, V.; Sabet, A.; Redin, E.; Kawasaki, K.; Shafer, M.; Karthaus, W. R.; Zaidi, S.; Zhan, Y. A.; Manoj, P.; Sridhar, H.; Shah, N. S.; Chow, A.; Bhanot, U. K.; Linkov, I.; Asher, M.; Yu, H. A.; Qiu, J.; de Stanchina, E.; Patel, R. A.; Morrissey, C.; Haffner, M. C.; Koche, R. P.; Sawyers, C. L.; Rudin, C. M.
Article Title: Exportin 1 inhibition prevents neuroendocrine transformation through SOX2 down-regulation in lung and prostate cancers
Abstract: 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.
Keywords: genetics; adenocarcinoma; metabolism; lung neoplasms; down-regulation; pathology; prostatic neoplasms; lung tumor; prostate tumor; lung; down regulation; soxb1 transcription factors; sox2 protein, human; transcription factor sox; small cell lung cancer; small cell lung carcinoma; enzalutamide; humans; human; male; selinexor; exportin 1 protein
Journal Title: Science Translational Medicine
Volume: 15
Issue: 707
ISSN: 1946-6234
Publisher: American Association for the Advancement of Science  
Date Published: 2023-08-02
Start Page: eadf7006
Language: English
DOI: 10.1126/scitranslmed.adf7006
PUBMED: 37531417
PROVIDER: scopus
PMCID: PMC10777207
DOI/URL:
Notes: The MSK Cancer Center Support Grant (P30 CA008748) is acknowledged in the PubMed record and PDF. Corresponding MSK author are Alvaro Quintanal-Villalonga and Charles M. Rudin -- Source: Scopus
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MSK Authors
  1. Charles L Sawyers
    226 Sawyers
  2. Helena Alexandra Yu
    287 Yu
  3. Umeshkumar Kapaldev Bhanot
    93 Bhanot
  4. Marina Asher
    36 Asher
  5. Irina Linkov
    75 Linkov
  6. Charles Rudin
    493 Rudin
  7. Richard Patrick Koche
    177 Koche
  8. Nisargbhai Sanjaykumar Shah
    29 Shah
  9. Juan   Qiu
    24 Qiu
  10. Vidushi Durani
    12 Durani
  11. Andrew Chow
    45 Chow
  12. Samir Zaidi
    27 Zaidi
  13. Yingqian Zhan
    37 Zhan
  14. Parvathy Manoj
    35 Manoj
  15. Amin Hamdy Mohammed Sabet
    7 Sabet
  16. Moniquetta Shafer
    3 Shafer