Molecular mechanism and therapeutic implications of selinexor (KPT-330) in liposarcoma

// Manoj Garg 1, 2, * , Deepika Kanojia 1, * , Anand Mayakonda 1 , Jonathan W. Said 3 , Ngan B. Doan 3 , Wenwen Chien 1 , Trivadi S Ganesan 2 , Linda Shyue Huey Chuang 1 , Nachiyappan Venkatachalam 1 , Erkan Baloglu 4 , Sharon Shacham 4 , Michael Kauffman 4 , H. Phillip Koeffler 1, 5, 6 1 Cancer Science Institute (CSI) of Singapore, National University of Singapore, Singapore 2 Department of Medical Oncology and Clinical Research, Cancer Institute (WIA), Adyar Chennai, India 3 Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, Los Angeles, CA, USA 4 Karyopharm Therapeutics Inc, Newton, MA, USA 5 Division of Hematology/Oncology, Cedars-Sinai Medical Center, University of California Los Angeles, School of Medicine, Los Angeles, CA, USA 6 National University Cancer Institute, National University Hospital, Singapore, Singapore * These authors contributed equally to this work Correspondence to: Manoj Garg, email: manoj.garg@cancerinstitutewia.org, nuscsimg@gmail.com Keywords: selinexor, IGFBP5, xenograft, cell cycle Received: July 29, 2016 Accepted: November 09, 2016 Published: November 21, 2016 ABSTRACT Exportin-1 mediates nuclear export of multiple tumor suppressor and growth regulatory proteins. Aberrant expression of exportin-1 is noted in human malignancies, resulting in cytoplasmic mislocalization of its target proteins. We investigated the efficacy of selinexor against liposarcoma cells both in vitro and in vivo . Exportin-1 was highly expressed in liposarcoma samples and cell lines as determined by immunohistochemistry, western blot, and immunofluorescence assay. Knockdown of endogenous exportin-1 inhibited proliferation of liposarcoma cells. Selinexor also significantly decreased cell proliferation as well as induced cell cycle arrest and apoptosis of liposarcoma cells. The drug also significantly decreased tumor volumes and weights of liposarcoma xenografts. Importantly, selinexor inhibited insulin-like growth factor 1 (IGF1) activation of IGF-1R/AKT pathway through upregulation of insulin-like growth factor binding protein 5 (IGFBP5). Further, overexpression and knockdown experiments showed that IGFBP5 acts as a tumor suppressor and its expression was restored upon selinexor treatment of liposarcoma cells. Selinexor decreased aurora kinase A and B levels in these cells and inhibitors of these kinases suppressed the growth of the liposarcoma cells. Overall, our study showed that selinexor treatment restored tumor suppressive function of IGFBP5 and inhibited aurora kinase A and B in liposarcoma cells supporting the usefulness of selinexor as a potential therapeutic strategy for the treatment of this cancer.