Protein kinases are arguably the most tractable candidates for development of new therapies to treat breast cancer. Recent data has shown that kinase cascades and signaling pathways are interrelated;inhibition by one pharmacologic kinase inhibitor has consequences beyond its cognate targets. Our hypothesis predicts that defining tumor kinome activity, and overall kinome-level response to therapy, will identify kinase signatures that can be targeted to accelerate development of new therapies for clinical trials. Project 5 uses an innovative new technology to study the kinome in the Basal-like and Claudin-low subtypes elucidating novel kinase targets and defining differences between these two subtypes. The technology affinity captures endogenous kinases and analyzes their activity with quantitative mass spectrometry, providing us with large scale, kinome activity profiles in tumors and cells. The quantitative proteomic assessment can also be used in dynamic tests determining what fraction of the kinome responds to inhibition of targeted kinases. The Raf- MEK-ERK pathway is often activated in Basal-like and Claudin-low breast cancer. For proof of concept, we defined the kinome response to MEK inhibition in a Claudin-low cell line and mouse tumor model of Basal- like/Claudin-low breast cancer. The tumor response to targeted kinase inhibition involved a highly reproducible induction and activation of multiple RTKs that contributed to drug resistance. Given the repertoire of RTKs whose expression and activity was induced with MEK inhibition, we predicted that a combination therapy that would

Public Health Relevance

Defining the activation state of kinases in patient tumors and response of tumor kinases to drug treatment identifies previously untargeted kinases essential for tumor growth and survival. Our experimental rationale will allow the design of new clinical trials involving combinations of kinase inhibitors based on properties of the kinome in Claudin-low and Basal-like breast cancer.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Specialized Center (P50)
Project #
Application #
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of North Carolina Chapel Hill
Chapel Hill
United States
Zip Code
Mobley, Robert J; Raghu, Deepthi; Duke, Lauren D et al. (2017) MAP3K4 Controls the Chromatin Modifier HDAC6 during Trophoblast Stem Cell Epithelial-to-Mesenchymal Transition. Cell Rep 18:2387-2400
Kohler, Racquel E; Gopal, Satish; Miller, Anna R et al. (2017) A framework for improving early detection of breast cancer in sub-Saharan Africa: A qualitative study of help-seeking behaviors among Malawian women. Patient Educ Couns 100:167-173
Valle, Carmina G; Deal, Allison M; Tate, Deborah F (2017) Preventing weight gain in African American breast cancer survivors using smart scales and activity trackers: a randomized controlled pilot study. J Cancer Surviv 11:133-148
Sharma, Priyanka; López-Tarruella, Sara; García-Saenz, Jose Angel et al. (2017) Efficacy of Neoadjuvant Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two Cohorts. Clin Cancer Res 23:649-657
Mullooly, Maeve; Yang, Hannah P; Falk, Roni T et al. (2017) Relationship between crown-like structures and sex-steroid hormones in breast adipose tissue and serum among postmenopausal breast cancer patients. Breast Cancer Res 19:8
Hoffman, Joshua D; Graff, Rebecca E; Emami, Nima C et al. (2017) Cis-eQTL-based trans-ethnic meta-analysis reveals novel genes associated with breast cancer risk. PLoS Genet 13:e1006690
Visvanathan, Kala; Fackler, MaryJo S; Zhang, Zhe et al. (2017) Monitoring of Serum DNA Methylation as an Early Independent Marker of Response and Survival in Metastatic Breast Cancer: TBCRC 005 Prospective Biomarker Study. J Clin Oncol 35:751-758
Zawistowski, Jon S; Bevill, Samantha M; Goulet, Daniel R et al. (2017) Enhancer Remodeling during Adaptive Bypass to MEK Inhibition Is Attenuated by Pharmacologic Targeting of the P-TEFb Complex. Cancer Discov 7:302-321
Bowerman, Charles J; Byrne, James D; Chu, Kevin S et al. (2017) Docetaxel-Loaded PLGA Nanoparticles Improve Efficacy in Taxane-Resistant Triple-Negative Breast Cancer. Nano Lett 17:242-248
Heng, Yujing J; Lester, Susan C; Tse, Gary Mk et al. (2017) The molecular basis of breast cancer pathological phenotypes. J Pathol 241:375-391

Showing the most recent 10 out of 548 publications