Therapeutic effects of XPO1 inhibition in thymic epithelial tumors

Fabio Conforti, Xu Zhang, Guanhua Rao, Tommaso De Pas, Yoko Yonemori, Jose Antonio Rodriguez, Justine N. McCutcheon, Raneen Rahhal, Anna T. Alberobello, Yisong Wang, Yu Wen Zhang, Udayan Guha, Giuseppe Giaccone

Research output: Contribution to journalArticle

Abstract

Exportin 1 (XPO1) mediates nuclear export of many cellular factors known to play critical roles in malignant processes, and selinexor (KPT-330) is the first XPO1-selective inhibitor of nuclear export compound in advanced clinical development phase for cancer treatment. We demonstrated here that inhibition of XPO1 drives nuclear accumulation of important cargo tumor suppressor proteins, including transcription factor FOXO3a and p53 in thymic epithelial tumor (TET) cells, and induces p53-dependent and -independent antitumor activity in vitro. Selinexor suppressed the growth of TET xenograft tumors in athymic nude mice via inhibition of cell proliferation and induction of apoptosis. Loss of p53 activity or amplification of XPO1 may contribute to resistance to XPO1 inhibitor in TET. Using mass spectrometry–based proteomics analysis, we identified a number of proteins whose abundances in the nucleus and cytoplasm shifted significantly following selinexor treatment in the TET cells. Furthermore, we found that XPO1 was highly expressed in aggressive histotypes and advanced stages of human TET, and high XPO1 expression was associated with poorer patient survival. These results underscore an important role of XPO1 in the pathogenesis of TET and support clinical development of the XPO1 inhibitor for the treatment of patients with this type of tumors.

Original languageEnglish
Pages (from-to)5614-5627
Number of pages14
JournalCancer Research
Volume77
Issue number20
DOIs
Publication statusPublished - Oct 15 2017

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Conforti, F., Zhang, X., Rao, G., De Pas, T., Yonemori, Y., Rodriguez, J. A., McCutcheon, J. N., Rahhal, R., Alberobello, A. T., Wang, Y., Zhang, Y. W., Guha, U., & Giaccone, G. (2017). Therapeutic effects of XPO1 inhibition in thymic epithelial tumors. Cancer Research, 77(20), 5614-5627. https://doi.org/10.1158/0008-5472.CAN-17-1323