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Selinexor (KPT-330) has antitumor activity against anaplastic thyroid carcinoma in vitro and in vivo and enhances sensitivity to doxorubicin. (Sci Rep, Aug 2017)

Garg M1,2, Kanojia D3, Mayakonda A3, Ganesan TS4, Sadhanandhan B4, Suresh S4, S S4, Nagare RP4, Said JW5, Doan NB5, Ding LW3, Baloglu E6, Shacham S6, Kauffman M6, Koeffler HP3,7.

Author information
1 Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore, Singapore. manoj.garg@cancerinstitutewia.org.
2 Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Adyar, Chennai, India. manoj.garg@cancerinstitutewia.org.
3 Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore, Singapore.
4 Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Adyar, Chennai, India.
5 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA, USA.
6 Karyopharm Therapeutics Inc, Newton, MA, 02459, USA.
7 Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California Los Angeles, School of Medicine, Los Angeles, CA, USA.

Abstract
Anaplastic thyroid carcinoma (ATC) is one of the most lethal malignancies having no effective treatment. Exportin-1 (XPO1) is the key mediator of nuclear export of many tumor suppressor proteins and is overexpressed in human cancers. In this study, we examined the therapeutic potential of selinexor (XPO1 inhibitor) against human ATC cells both in vitro and in vivo. Here, we showed that XPO1 is robustly expressed in primary ATC samples and human ATC cell lines. Silencing of XPO1 by either shRNA or selinexor significantly reduced cellular growth and induced cell cycle arrest, apoptosis of ATC cells by altering the protein expression of cancer-related genes. Moreover, selinexor significantly inhibited tumor growth of ATC xenografts. Microarray analysis showed enrichment of DNA replication, cell cycle, cell cycle checkpoint and TNF pathways in selinexor treated ATC cells. Importantly, selinexor decreased AXL and GAS6 levels in CAL62 and HTH83 cells and suppressed the phosphorylation of downstream targets of AXL signaling such as AKT and P70S6K. Finally, a combination of selinexor with doxorubicin demonstrated a synergistic decrease in the cellular proliferation of several ATC cells. These results provide a rationale for investigating the efficacy of combining selinexor and doxorubicin therapy to improve the outcome of ATC patients.

PMID: 28852098