Oops, you're using an old version of your browser so some of the features on this page may not be displaying properly.

MINIMAL Requirements: Google Chrome 24+Mozilla Firefox 20+Internet Explorer 11Opera 15–18Apple Safari 7SeaMonkey 2.15-2.23

Poster display session

2884 - Combinatorial Inhibition of mTOR and Exportin-1 (XPO1) Represses Cell Survival Via Metabolic Modulation of Pro-survival Pathways in Mantle Cell Lymphomas

Date

11 Sep 2017

Session

Poster display session

Presenters

Kazumasa Sekihara

Citation

Annals of Oncology (2017) 28 (suppl_5): v1-v21. 10.1093/annonc/mdx361

Authors

K. Sekihara1, K. Saitoh1, H. Yang1, T. Miida1, M. Andreeff2, Y. Tabe1

Author affiliations

  • 1 Clinical Laboratory Medicine, Juntendo University School of Medicine, 113-0033 - Tokyo/JP
  • 2 Department Of Leukemia, The University of Texas MD Anderson Cancer Center, Houston/US
More

Resources

Abstract 2884

Background

MCL is an aggressive B-cell lymphoma with aberrant expression of several oncogenic effectors and requiring novel anticancer strategies. The nuclear transporter exportin-1 (XPO1) is highly expressed in MCL and is critical for cancer survival and proliferation. mTOR signaling is frequently activated and an important therapeutic target in MCL. In this study, we investigated the antitumor effects and molecular/metabolic changes induced by combined with dual mTOR inhibitor AZD-2014 and XPO1 inhibitor KPT-185 on MCL cells under the hypothesis that mTOR inhibition by AZD-2014 represses KPT-185 inducedupregulation of glycolysis.

Methods

Four MCL cell lines (Jeko-1, X138, JVM-2, and MINO), primary MCL cells, and normal bone marrow samples were utilized. Cell viability was evaluated by MTT assay. Cell cycle and apoptosis were determined by flow cytometric analysis. cDNA array, iTRAQ proteomic, immunoblotting and metabolome analysis using CE-TOF-MS were also performed.

Results

AZD-2014 enhanced KPT-185-induced the inhibition of cell growth and repression of cell viability in MCL cells but not in normal bone marrow cells. Different mTOR inhibitors (AZD-8055 and MLN0128) demonstrated similar effects. AZD-2014+KPT-185 decreased expression of the oncogenic mediator c-Myc andthe translational/transcriptional network regulator HSF1as detected by immunoblotting. iTRAQ proteomic analysis demonstrated thatthe combination caused repression of ribosomal biogenesis. Treatment with either AZD-2014 or KPT-185 depressed phospho-S6.CET-OF-MS metabolite assay showed that AZD-2014+KPT-185inhibited theKrebs cycle, and that AZD-2014 effectively repressed KPT-185-induced upregulation of glycolysis. cDNA array detected downregulation of NOD2which is known to trigger activation of MAP kinases and of NF-kappa-B signaling. Moreover, AZD-2014+KPT-185 activated AMPK, an energy stress marker in a cell type-dependent manner.

Conclusions

Our findings indicated that the combinatorial inhibition of mTOR and XPO1 identifies a novel synthetic lethality mechanism that could be exploited clinically, following satisfactory completion of pre-clinical in vivo studies.

Clinical trial identification

Legal entity responsible for the study

Yoko Tabe

Funding

None

Disclosure

All authors have declared no conflicts of interest.

This site uses cookies. Some of these cookies are essential, while others help us improve your experience by providing insights into how the site is being used.

For more detailed information on the cookies we use, please check our Privacy Policy.

Customise settings
  • Necessary cookies enable core functionality. The website cannot function properly without these cookies, and you can only disable them by changing your browser preferences.