Definition of PKC-α, CDK6, and MET as Therapeutic Targets in Triple-Negative Breast Cancer

被引：60

作者：

Hsu, Yi-Hsin ^{[1
]}

Yao, Jun ^{[1
]}

Chan, Li-Chuan ^{[1
,2
]}

Wu, Ting-Jung ^{[1
,3
]}

Hsu, Jennifer L. ^{[1
,4
,5
,6
]}

Fang, Yueh-Fu ^{[1
,7
]}

Wei, Yongkun ^{[1
]}

Wu, Yun ^{[8
]}

Huang, Wen-Chien ^{[9
]}

Liu, Chien-Liang ^{[9
]}

Chang, Yuan-Ching ^{[9
]}

Wang, Ming-Yang ^{[1
,10
]}

Li, Chia-Wei ^{[1
]}

Shen, Jia ^{[1
,2
]}

Chen, Mei-Kuang ^{[2
]}

Sahin, Aysegul A. ^{[8
]}

Sood, Anil ^{[2
,11
]}

Mills, Gordon B. ^{[2
,12
]}

Yu, Dihua ^{[1
,2
]}

Hortobagyi, Gabriel N. ^{[13
]}

Hung, Mien-Chie ^{[1
,2
,4
,5
,6
]}

机构：

[1] Univ Texas MD Anderson Canc Ctr, Dept Mol & Cellular Oncol, Houston, TX 77030 USA

[2] Univ Texas, Grad Sch Biomed Sci Houston, Houston, TX USA

[3] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp Linkou, Dept Gen Surg, Taipei, Taiwan

[4] China Med Univ, Grad Inst Canc Biol, Taichung, Taiwan

[5] China Med Univ, Ctr Mol Med, Taichung, Taiwan

[6] Asia Univ, Dept Biotechnol, Taichung, Taiwan

[7] Chang Gung Univ, Coll Med, Chang Gung Mem Hosp Linkou, Dept Internal Med, Taipei, Taiwan

[8] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[9] Mackay Mem Hosp, Mackay Jr Coll Med Nursing & Management, Dept Surg, Taipei, Taiwan

[10] Natl Taiwan Univ Hosp, Dept Surg, Taipei 100, Taiwan

[11] Univ Texas MD Anderson Canc Ctr, Dept Gynecol Oncol & Reprod Med, Houston, TX 77030 USA

[12] Univ Texas MD Anderson Canc Ctr, Dept Syst Biol, Houston, TX 77030 USA

[13] Univ Texas MD Anderson Canc Ctr, Dept Breast Med Oncol, Houston, TX 77030 USA

来源：

CANCER RESEARCH | 2014年 / 74卷 / 17期

关键词：

PROTEIN-KINASE; INHIBITOR OLAPARIB; ANALYSIS TOOL; STEM-CELLS; PHASE-I; COMBINATION; EXPRESSION; SURVIVAL; TRIAL; IDENTIFICATION;

D O I：

10.1158/0008-5472.CAN-14-0584

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

Triple-negative breast cancer (TNBC) is a highly heterogeneous and recurrent subtype of breast cancer that lacks an effective targeted therapy. To identify candidate therapeutic targets, we profiled global gene expression in TNBC and breast tumor-initiating cells with a patient survival dataset. Eight TNBC-related kinases were found to be overexpressed in TNBC cells with stem-like properties. Among them, expression of PKC-alpha. MET, and CHK6 correlated with poorer survival outcomes. In cases coexpressing two of these three kinases, survival rates were lower than in cases where only one of these kinases was expressed. In functional tests, two-drug combinations targeting these three kinases inhibited TNBC cell proliferation and turnorigenic potential in a cooperative manner. A combination of PKC-alpha-MET inhibitors also attenuated tumor growth in a cooperative manner in vivo. Our findings define three kinases critical for TNBC growth and offer a preclinical rationale for their candidacy as effective therapeutic targets in treating TNBC. (C)2014 AACR

引用

页码：4822 / 4835

页数：14

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