Members of the nuclear-factor-?B (NF-?B) transcription factor family play a central role in regulating many physiological processes including innate and adaptive immunity. In addition, accumulating evidence suggests that inappropriate activation of NF-?B occurs in many types of human cancers. Indeed, genome characterization studies have uncovered genetic alterations involving many components of the NF-?B signaling cascade in both hematopoietic and epithelial cancers, and accumulating evidence indicates that NF-?B signaling contributes to resistance to targeted cancer therapy. Using integrated genomic approaches, we identified the two closely related, non-canonical inhibitors of ?B kinase, IKK? (IKBKE, IKKi) and TBK1, as an amplified breast cancer oncogene and an essential gene in KRAS-driven human cancers, respectively. During the past funding period, we have used biochemical, genetic and molecular biological approaches to solve the structure of these two IKKs and identify substrates of these two IKKs critical for cell transformation. We have also identified K63-linked ubiquitination as one mechanism of regulation of these IKKs, essential for their tumorigenic function. These observations provide new insights into the function of these IKKs in both innate and oncogenic contexts. Based on these observations, this proposal focuses on delineate the mechanism(s) by which these immune regulators contribute to malignant transformation and to credential IKK? and TBK1 inhibitors. We will perform mechanistic studies critical to understanding how perturbing IKK? function affects tumor maintenance and will develop small molecule inhibitors of IKK?. Specifically, biochemical, genetic, molecular biological and pharmacologic approaches will be applied to interrogate the regulation of IKK? in both immune and oncogenic contexts, to identify effector pathways that mediate IKK?-induced cell transformation and to validate IKK? inhibitors preclinically. Investigating the regulation and function of IKK? in breast cancer development will not only enhance our mechanistic understanding of this non-canonical IKK regulator but will also clarify the role of NF-?B signaling in the development of human epithelial cancers. In addition, these studies will provide a foundation for strategies to target this kinase oncogene therapeutically.

Public Health Relevance

Although significant progress has been made in the diagnosis and treatment of breast cancer, we lack curative targeted therapies for many advanced stage breast cancers. This proposal focuses on deciphering the role of a kinase oncogene in breast cancer pathogenesis. These biochemical, cell and pharmacologic studies will not only provide insight into the biology of this kinase oncogene but will serve as a foundation for translational studies for the development of novel therapeutic agents.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
2R01CA130988-06A1
Application #
8758857
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Yassin, Rihab R,
Project Start
2007-12-01
Project End
2019-07-31
Budget Start
2014-08-11
Budget End
2015-07-31
Support Year
6
Fiscal Year
2014
Total Cost
$371,117
Indirect Cost
$109,772
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
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