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

• Published in: Cancer research (Chicago, Ill.) Ill.), 2014-09, Vol.74 (17), p.4822-4835
• Main Authors: HSU, Yi-Hsin, JUN YAO, CHANG, Yuan-Ching, WANG, Ming-Yang, LI, Chia-Wei, JIA SHEN, CHEN, Mei-Kuang, SAHIN, Aysegul A, SOOD, Anil, MILLS, Gordon B, DIHUA YU, HORTOBAGYI, Gabriel N, CHAN, Li-Chuan, HUNG, Mien-Chie, WU, Ting-Jung, HSU, Jennifer L, FANG, Yueh-Fu, YONGKUN WEI, YUN WU, HUANG, Wen-Chien, LIU, Chien-Liang
• Format: Article
• Language: English
• Subjects: Animals; Antineoplastic agents; Biological and medical sciences; Cell Line, Tumor; Cell Proliferation - drug effects; Cell Proliferation - genetics; Cyclin-Dependent Kinase 6 - genetics; Female; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - genetics; Gynecology. Andrology. Obstetrics; Humans; Mammary gland diseases; MCF-7 Cells; Medical sciences; Mice; Mice, Nude; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Neoplastic Stem Cells - drug effects; Pharmacology. Drug treatments; Protein Kinase C-alpha - genetics; Protein Kinase Inhibitors - pharmacology; Protein-Serine-Threonine Kinases - genetics; Proto-Oncogene Proteins c-met - genetics; Survival Rate; Triple Negative Breast Neoplasms - drug therapy; Triple Negative Breast Neoplasms - genetics; Tumors
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/0008-5472.CAN-14-0584

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-α, MET, and CDK6 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 tumorigenic potential in a cooperative manner. A combination of PKC-α-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.