Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer

Yi Hsin Hsu, Jun Yao, Li Chuan Chan, Ting Jung Wu, Jennifer L. Hsu, Yueh Fu Fang, Yongkun Wei, Yun Wu, Wen Chien Huang, Chien Liang Liu, Yuan Ching Chang, Ming Yang Wang, Chia Wei Li, Jia Shen, Mei Kuang Chen, Aysegul A. Sahin, Anil Sood, Gordon B. Mills, Dihua Yu, Gabriel N. HortobagyiMien Chie Hung

Research output: Contribution to journalArticle

39 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)4822-4835
Number of pages14
JournalCancer Research
Volume74
Issue number17
DOIs
StatePublished - Sep 1 2014
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Hsu, Y. H., Yao, J., Chan, L. C., Wu, T. J., Hsu, J. L., Fang, Y. F., Wei, Y., Wu, Y., Huang, W. C., Liu, C. L., Chang, Y. C., Wang, M. Y., Li, C. W., Shen, J., Chen, M. K., Sahin, A. A., Sood, A., Mills, G. B., Yu, D., ... Hung, M. C. (2014). Definition of PKC-α, CDK6, and MET as therapeutic targets in triple-negative breast cancer. Cancer Research, 74(17), 4822-4835. https://doi.org/10.1158/0008-5472.CAN-14-0584