Targeting mantle cell lymphoma metabolism and survival through simultaneous blockade of mTOR and nuclear transporter exportin-1

// Kazumasa Sekihara 1, 2 , Kaori Saitoh 1 , Lina Han 3 , Stefan Ciurea 3 , Shinichi Yamamoto 1, 2 , Mika Kikkawa 4 , Saiko Kazuno 4 , Hikari Taka 4 , Naoko Kaga 4 , Hajime Arai 4 , Takashi Miida 1 , Michael Andreeff 3 , Marina Konopleva 3 , Yoko Tabe 1, 3, 5 1 Department of Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan 2 Leading Center for the Development and Research of Cancer Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan 3 Section of Molecular Hematology and Therapy, Department of Leukemia, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA 4 Laboratory of Proteomics and Biomolecular Science, Research Support Center, Juntendo University Graduate School of Medicine, Tokyo, Japan 5 Department of Next Genertion Hematology Laboratory Medicine, Juntendo University Graduate School of Medicine, Tokyo, Japan Correspondence to: Yoko Tabe, email: tabe@juntendo.ac.jp Keywords: mantle cell lymphoma, mTORC1/2, selective inhibitor of nuclear export, XPO1, metabolism Received: May 31, 2016      Accepted: March 16, 2017      Published: March 27, 2017 ABSTRACT Mantle cell lymphoma (MCL) is an aggressive B-cell lymphoma with poor prognosis, characterized by aberrant expression of growth-regulating and oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is associated with its pathogenesis. mTOR signaling, a central regulator of cell metabolism, is frequently activated in MCL and is also an important therapeutic target in this cancer. This study investigated the antitumor effects and molecular/metabolic changes induced by the combination of the small-molecule selective inhibitor XPO1 inhibitor KPT-185 and the dual mTORC1/2 kinase inhibitor AZD-2014 on MCL cells. AZD-2014 enhanced the KPT-185–induced inhibition of cell growth and repression of cell viability. The combination of KPT-185 and AZD-2014 downregulated c-Myc and heat shock factor 1 (HSF1) with its target heat shock protein 70 (HSP70). As a consequence, the combination caused repression of ribosomal biogenesis demonstrated by iTRAQ proteomic analyses. Metabolite assay by CETOF-MS showed that AZD-2014 enhanced the KPT-185–induced repression of MCL cellular energy metabolism through the TCA (Krebs) cycle, and further repressed KPT-185–caused upregulation of glycolysis. Thus the simultaneous inhibition of XPO1 and mTOR signaling is a novel and promising strategy targeting prosurvival metabolism in MCL.