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 Basallike/ 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 """"""""broaden"""""""" the kinase targeting sufficiently to produce significant therapeutic benefit. The combination therapy increased apoptosis and tumor regression in genetically-engineered models of TNBC. The response was significant compared to either drug alone. Thus, we created a signature of therapeutic response resistance allowing a rational prediction of combinatorial therapies. This approach will be used to create signatures of kinome response to MEK inhibitors, PI3K inhibitors and other kinase inhibitors (both clinically available and in development) using Claudin-low and Basal-like breast cancer cells, GEMMs and patient-derived xenografts. A window trial in patients with TNBC, performed in collaboration with GlaxoSmithKline using their MEK inhibitor, is currently in clinical trials. The trial will provide dynamic data for comparison to that obtained in cell lines, GEMMs and patient-derived xenografts. The window trial will be first to assess kinome reprogramming with the goal of potentially allowing rational prediction of combination therapies in a patient.

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)
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
Cheng, Ting-Yuan David; Ambrosone, Christine B; Hong, Chi-Chen et al. (2016) Genetic variants in the mTOR pathway and breast cancer risk in African American women. Carcinogenesis 37:49-55
Ruiz-Narváez, Edward A; Haddad, Stephen A; Lunetta, Kathryn L et al. (2016) Gene-based analysis of the fibroblast growth factor receptor signaling pathway in relation to breast cancer in African American women: the AMBER consortium. Breast Cancer Res Treat 155:355-63
Sun, Xuezheng; Nichols, Hazel B; Tse, Chiu-Kit et al. (2016) Association of Parity and Time since Last Birth with Breast Cancer Prognosis by Intrinsic Subtype. Cancer Epidemiol Biomarkers Prev 25:60-7
Murphy, Caitlin C; Sandler, Robert S; Sanoff, Hanna K et al. (2016) Decrease in Incidence of Colorectal Cancer Among Individuals 50 Years or Older After Recommendations for Population-based Screening. Clin Gastroenterol Hepatol :
Li, Hui; Zhu, Yitan; Burnside, Elizabeth S et al. (2016) Quantitative MRI radiomics in the prediction of molecular classifications of breast cancer subtypes in the TCGA/TCIA data set. NPJ Breast Cancer 2:
Nichols, Hazel B; Bowles, Erin J A; Islam, Jessica et al. (2016) Tamoxifen Initiation After Ductal Carcinoma In Situ. Oncologist 21:134-40
He, Zhijian; Wan, Xiaomeng; Schulz, Anita et al. (2016) A high capacity polymeric micelle of paclitaxel: Implication of high dose drug therapy to safety and in vivo anti-cancer activity. Biomaterials 101:296-309
Johnson, Amy R; Qin, Yuanyuan; Cozzo, Alyssa J et al. (2016) Metabolic reprogramming through fatty acid transport protein 1 (FATP1) regulates macrophage inflammatory potential and adipose inflammation. Mol Metab 5:506-26
Roberts, Megan C; Weinberger, Morris; Dusetzina, Stacie B et al. (2016) Racial Variation in the Uptake of Oncotype DX Testing for Early-Stage Breast Cancer. J Clin Oncol 34:130-8
Hertz, Daniel L; Deal, Allison; Ibrahim, Joseph G et al. (2016) Tamoxifen Dose Escalation in Patients With Diminished CYP2D6 Activity Normalizes Endoxifen Concentrations Without Increasing Toxicity. Oncologist 21:795-803

Showing the most recent 10 out of 500 publications