Oncotarget

Research Papers:

Staurosporine, an inhibitor of hormonally up-regulated neu-associated kinase

Joelle N. Zambrano, Christina J. Williams, Carly Bess Williams, Lonzie Hedgepeth, Pieter Burger, Tinslee Dilday, Scott T. Eblen, Kent Armeson, Elizabeth G. Hill and Elizabeth S. Yeh _

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Oncotarget. 2018; 9:35962-35973. https://doi.org/10.18632/oncotarget.26311

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Abstract

Joelle N. Zambrano1, Christina J. Williams1, Carly Bess Williams1, Lonzie Hedgepeth1, Pieter Burger2,3, Tinslee Dilday1, Scott T. Eblen1, Kent Armeson4, Elizabeth G. Hill4 and Elizabeth S. Yeh1

1Department of Cell and Molecular Pharmacology and Experimental Therapeutics, Medical University of South Carolina, Charleston, SC 29425, USA

2Department of Drug Discovery and Biomedical Sciences, Medical University of South Carolina, Charleston, SC 29425, USA

3Department of Chemistry, Emory University, Atlanta, GA 30322, USA

4Department of Public Health Sciences, Medical University of South Carolina, Charleston, SC 29425, USA

Correspondence to:

Elizabeth S. Yeh, email: yeh@musc.edu

Keywords: HUNK; staurosporine; HER2; breast cancer; resistance

Received: April 16, 2018     Accepted: October 21, 2018     Published: November 13, 2018

ABSTRACT

HUNK is a protein kinase that is implicated in HER2-positive (HER2+) breast cancer progression and resistance to HER2 inhibitors. Though prior studies suggest there is therapeutic potential for targeting HUNK in HER2+ breast cancer, pharmacological agents that target HUNK are yet to be identified. A recent study showed that the broad-spectrum kinase inhibitor staurosporine binds to the HUNK catalytic domain, but the effect of staurosporine on HUNK enzymatic activity was not tested. We now show that staurosporine inhibits the kinase activity of a full length HUNK protein. Our findings further suggest that inhibiting HUNK with staurosporine has a strong effect on suppressing cell viability of HER2/neu mammary and breast cancer cells, which express high levels of HUNK protein and are dependent on HUNK for survival. Significantly, we use in vitro and in vivo methods to show that staurosporine synergizes with the HER2 inhibitor lapatinib to restore sensitivity toward HER2 inhibition in a HER2 inhibitor resistant breast cancer model. Collectively, these studies indicate that pharmacological inhibition of HUNK kinase activity has therapeutic potential for HER2+ breast cancers, including HER2+ breast cancers that have developed drug resistance.


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