Oncotarget

Research Papers:

XPO1 inhibition by selinexor induces potent cytotoxicity against high grade bladder malignancies

Han Bit Baek, Alan P. Lombard, Stephen J. Libertini, Aleida Fernandez-Rubio, Ruth Vinall, Regina Gandour-Edwards, Rachel Nakagawa, Kathleen Vidallo, Kristine Nishida, Salma Siddiqui, Hiromi Wettersten, Yosef Landesman, Robert H. Weiss, Paramita M. Ghosh and Maria Mudryj _

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Oncotarget. 2018; 9:34567-34581. https://doi.org/10.18632/oncotarget.26179

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Abstract

Han Bit Baek1,2,*, Alan P. Lombard1,2,3,*, Stephen J. Libertini1,2, Aleida Fernandez-Rubio2, Ruth Vinall4, Regina Gandour-Edwards5, Rachel Nakagawa2, Kathleen Vidallo2, Kristine Nishida2, Salma Siddiqui1, Hiromi Wettersten6, Yosef Landesman7, Robert H. Weiss1,6, Paramita M. Ghosh1,8 and Maria Mudryj1,2

1Veterans Affairs-Northern California Health Care System, Mather, CA, USA

2Department of Medical Microbiology and Immunology, University of California Davis, Davis, CA, USA

3Biochemistry, Molecular, Cellular, and Developmental Biology Graduate Group and Biotechnology Program, University of California Davis, Davis, CA, USA

4California Northstate College of Pharmacy, Elk Grove, CA, USA

5Department of Pathology and Laboratory Medicine, University of California Davis, Sacramento, CA, USA

6Department of Internal Medicine, University of California Davis, Davis, CA, USA

7Karyopharm Therapeutics, Newton, MA, USA

8Department of Urology, University of California Davis, Sacramento, CA, USA

*These authors contributed equally to this work

Correspondence to:

Maria Mudryj, email: mmudryj@ucdavis.edu

Keywords: bladder cancer; XPO1; retinoblastoma; selinexor; cell cycle

Received: August 01, 2018     Accepted: September 15, 2018     Published: October 02, 2018

ABSTRACT

Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner. The decrease in cell viability was due to an induction of apoptosis and cell cycle arrest. These results were recapitulated in in vivo studies where selinexor decreased tumor growth. Tumors treated with selinexor expressed lower levels of XPO1, cyclin A, cyclin B, and CDK2 and increased levels of RB and CDK inhibitor p27, a result that is consistent with growth arrest. Cells expressing wildtype RB, a potent tumor suppressor that promotes growth arrest and apoptosis, were most susceptible to selinexor. Cell fractionation and immunofluorescence studies showed that selinexor treatment increased nuclear RB levels and mechanistic studies revealed that RB ablation curtailed the response to the drug. Conversely, limiting CDK4/6 dependent RB phosphorylation by palbociclib was additive with selinexor in reducing bladder tumor cell viability, confirming that RB activity has a role in the response to XPO1 inhibition. These results provide a rationale for XPO1 inhibition as a novel strategy for the treatment of bladder malignancies.


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