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.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Specialized Center (P50)
Project #
2P50CA058223-19A1
Application #
8389745
Study Section
Special Emphasis Panel (ZCA1-RPRB-0 (M1))
Project Start
1997-08-05
Project End
2017-08-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
19
Fiscal Year
2012
Total Cost
$195,169
Indirect Cost
Name
University of North Carolina Chapel Hill
Department
Type
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599
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