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

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

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

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

Journal article

Open access

Peer reviewed

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

Jie Jiang, Fu Gui, Zhixiang He, Li Li, Yunzhan Li, Shunying Li, Xinrui Wu, Zhou Deng, Xihuan Sun, Xiaoxing Huang, …

Cancer research (Chicago, Ill.), Vol.77(1), pp.175-186

01/01/2017

DOI: https://doi.org/10.1158/0008-5472.CAN-16-1038

PMID: 27758886

Abstract

Animals

Antineoplastic Agents - pharmacology

Breast Neoplasms - genetics

Breast Neoplasms - mortality

Breast Neoplasms - pathology

Cell Line, Tumor

Cell Proliferation - drug effects

Female

Humans

Kaplan-Meier Estimate

Mice

Mice, Inbred BALB C

Mice, Nude

Neoplasm Proteins - antagonists & inhibitors

Prognosis

Protein Kinase Inhibitors - pharmacology

Protein-Tyrosine Kinases - antagonists & inhibitors

Transcriptome

Xenograft Model Antitumor Assays

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.

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

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Title: Targeting BRK-Positive Breast Cancers with Small-Molecule Kinase Inhibitors
Creators: Jie Jiang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Fu Gui - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Zhixiang He - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Li Li - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Yunzhan Li - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Shunying Li - Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
Xinrui Wu - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Zhou Deng - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Xihuan Sun - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Xiaoxing Huang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Wei Huang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Shang Han - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Ting Zhang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Zheng Wang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Bo Jiao - State Key Laboratory for Medical Genomics, Shanghai Institute of Hematology, Collaborative Innovation Center of Hematology, Collaborative Innovation Center of System Biology, Ruijin Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
Siyang Song - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Hongrui Wang - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Lanfen Chen - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Dawang Zhou - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China
Qiang Liu - Breast Tumor Center, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou, China
Ruibao Ren - Department of Biology, Brandeis University, Waltham, Massachusetts
Jianming Zhang - Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. xmdeng@xmu.edu.cn Jzhang14@mgh.harvard.edu ren@brandeis.edu
Xianming Deng - State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Xiamen, Fujian, China. xmdeng@xmu.edu.cn Jzhang14@mgh.harvard.edu ren@brandeis.edu
Publication Details: Cancer research (Chicago, Ill.), Vol.77(1), pp.175-186
Identifiers: 9924014243701921
Academic Unit: Rosenstiel Basic Medical Sciences Research Center; Department of Biology
Language: English
Resource Type: Journal article

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

Abstract

UN Sustainable Development Goals (SDGs)

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