Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors.

Jie Jiang,Ruibao Ren,Wei Huang,Hongrui Wang,Shunying Li,Fu Gui,Xihuan Sun,Xiaoxing Huang,Lanfen Chen,Ting Zhang,Zheng Wang,Li Li,Qiang Liu,Zhixiang He,Xinrui Wu,Xianming Deng,Shang Han,Jianming Zhang,Dawang Zhou,Bo Jiao,Yunzhan Li,Shuai Song ,Zhou J Deng

doi:10.1158/0008-5472.can-16-1038

Abstract

Approximately 80% of breast cancers overexpress the kinase breast tumor kinase (BRK)/protein tyrosine kinase 6, which has various oncogenic roles in breast cancer cell proliferation, survival, and migration. However, BRK inhibitors have yet to be explored as possible therapeutic tools. In this study, we used a parallel compound-centric approach to discover a new class of pharmaceutical agents, exemplified by XMU-MP-2, as potent and selective BRK inhibitors. XMU-MP-2 exhibited target-specific inhibition of BRK kinase activity and disrupted signaling pathways mediated by this activity, thereby reducing proliferation in BRK-positive breast cancer cells. In mouse xenograft models, XMU-MP-2 repressed the growth of tumors driven by oncogenic BRK, including BRK-transformed Ba/F3 cells and BRK-positive breast cancer cells. Notably, XMU-MP-2 cooperated strongly with HER2 inhibitor or ER blockade to block breast cancer cell proliferation in vitro and in vivo Overall, our findings offer a preclinical proof of concept for therapeutic targeting of the BRK kinase in breast cancer. Cancer Res; 77(1); 175-86. ©2016 AACR.

Highlights

Protein kinase inhibitors have been one of the major targeted cancer therapeutics since the discovery of "Magic bullet" imatinib for chronic myeloid leukemia [1]
Www.aacrjournals.org combining with relevant target therapeutics could address the challenge of the treatment for aggressive ER/PR/HER2 negative breast cancers or overcome the drug resistance against ER/PR/ HER2-targeted therapy. We address those fundamental questions in targeting breast tumor kinase (BRK)-positive breast cancer by developing XMU-MP-2, a small-molecule inhibitor of BRK that selectively inhibits the kinase activity of BRK and its downstream signaling, results in significant antiproliferation potency on oncogenic BRK transformed Ba/F3 cells and BRK overexpressing breast cancer cells
We further examined whether the antiproliferative potency of XMU-MP-2 against BRK-positive cancer cells was accompanied by inhibition of cellular BRK tyrosine kinase activity

Summary

Introduction

Protein kinase inhibitors have been one of the major targeted cancer therapeutics since the discovery of "Magic bullet" imatinib for chronic myeloid leukemia [1]. Albeit success of kinase inhibitors widely used for variety of cancers, there are many functional important kinases left untouched because of either the uncertainty of pharmacologic relevance of those kinases as therapeutic targets in cancer, or lack of kinase-specific inhibitors. Of particular interest is breast tumor kinase (BRK). There is ample evidence to suggest the oncogenic role of BRK in variety cancers, yet none of BRK kinase–directed approach exists in clinic [2, 3]. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/).

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