Oncotarget

Research Papers:

Selinexor reduces the expression of DNA damage repair proteins and sensitizes cancer cells to DNA damaging agents

Trinayan Kashyap _, Christian Argueta, Thaddeus Unger, Boris Klebanov, Sophia Debler, William Senapedis, Marsha L. Crochiere, Margaret S. Lee, Michael Kauffman, Sharon Shacham and Yosef Landesman

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Oncotarget. 2018; 9:30773-30786. https://doi.org/10.18632/oncotarget.25637

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Abstract

Trinayan Kashyap1, Christian Argueta1, Thaddeus Unger1, Boris Klebanov1, Sophia Debler1, William Senapedis1, Marsha L. Crochiere1, Margaret S. Lee1, Michael Kauffman1, Sharon Shacham1 and Yosef Landesman1

1Karyopharm Therapeutics Inc., Newton, MA 02459, USA

Correspondence to:

Trinayan Kashyap, email: tkashyap@karyopharm.com

Keywords: DNA damage repair; selinexor; nuclear export; chemotherapy

Received: March 21, 2018     Accepted: June 01, 2018     Published: July 20, 2018

ABSTRACT

Introduction: The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents (DDAs) in cancer cells.

Results: Selinexor reduced the expression of DNA damage repair (DDR) proteins. This did not induce significant DNA damage in tested cell lines. Inhibition of DDR protein expression resulted in enhanced cancer cell death when cells were pretreated with DDAs. In contrast, enhanced cell death was not detected in cells that were pretreated with selinexor then with DDAs. In vivo, single-agent selinexor, docetaxel, or cisplatin treatment resulted in 66.7%, 51.5%, and 26.6% tumor growth inhibition (TGI), respectively, in an MDA-MB-231 xenograft model. Consequently, combination treatment with docetaxel or cisplatin followed by selinexor in vivo resulted in 93.9% and 103.4% TGI, respectively. Immunohistochemical staining and immunoblot analysis of tumor sections confirmed reduced expression of DDR proteins.

Conclusion: Selinexor treatment inhibited DDR mechanisms in cancer cell lines and therefore potentiated DNA damage-based therapy. The sequential combination of DDAs followed by selinexor increased cancer cell death. This combination is superior to each individual therapy and has a mechanistic rationale as a novel anticancer strategy.

Methods: Cancer cells treated with selinexor ± DDAs were analyzed using reverse phase protein arrays, immunoblots, quantitative PCR and immunofluorescence. Mice bearing MDA-MB-231 tumors were treated with subtherapeutic doses of selinexor, cisplatin, docetaxel and selinexor in combination with either cisplatin or docetaxel. Tumor growth was evaluated for 25 days.


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