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

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

doi:10.18632/oncotarget.26311

Joelle N Zambrano, Christina J Williams + Show 8 more

Open Access

https://doi.org/10.18632/oncotarget.26311

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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.

Highlights

Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer accounts for 15–30% of all breast cancer diagnoses
Recent reports have shown that using shRNA to impair Hormonally Up-regulated Neu-associated Kinase (HUNK) expression suppresses in vivo tumor growth of orthotopic mammary tumors generated from HER2+ breast cancer cells that are resistant to HER2 inhibitors [9, 10]
Our findings show that STU reduces cell viability of HER2/ neu+ breast and mammary tumor cells as well as HER2inhibitor resistant HER2+ human breast cancer cells, which are dependent on HUNK as a pro-survival signaling molecule

Summary

Introduction

Human Epidermal Growth Factor Receptor 2-positive (HER2+) breast cancer accounts for 15–30% of all breast cancer diagnoses This subtype is associated with poor prognosis and it is reported that there is a high incidence of resistance to clinically-available HER2 inhibitors [1,2,3,4,5]. Recent reports have shown that using shRNA to impair HUNK expression suppresses in vivo tumor growth of orthotopic mammary tumors generated from HER2+ breast cancer cells that are resistant to HER2 inhibitors [9, 10]. These studies suggest that targeting HUNK could be advantageous in the treatment of HER2+ breast cancer, in cases where HER2 inhibitor resistance is indicated

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