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 #
5R01CA130988-09
Application #
9308875
Study Section
Basic Mechanisms of Cancer Therapeutics Study Section (BMCT)
Program Officer
Yassin, Rihab R
Project Start
2009-03-01
Project End
2019-07-31
Budget Start
2017-08-01
Budget End
2018-07-31
Support Year
9
Fiscal Year
2017
Total Cost
Indirect Cost
Name
Dana-Farber Cancer Institute
Department
Type
DUNS #
076580745
City
Boston
State
MA
Country
United States
Zip Code
02215
Horn, Heiko; Lawrence, Michael S; Chouinard, Candace R et al. (2018) NetSig: network-based discovery from cancer genomes. Nat Methods 15:61-66
Li, Ji; Choi, Peter S; Chaffer, Christine L et al. (2018) An alternative splicing switch in FLNB promotes the mesenchymal cell state in human breast cancer. Elife 7:
Aguirre, Andrew J; Hahn, William C (2018) Synthetic Lethal Vulnerabilities in KRAS-Mutant Cancers. Cold Spring Harb Perspect Med 8:
Zwang, Yaara; Jonas, Oliver; Chen, Casandra et al. (2017) Synergistic interactions with PI3K inhibition that induce apoptosis. Elife 6:
Kim, Jong Wook; Abudayyeh, Omar O; Yeerna, Huwate et al. (2017) Decomposing Oncogenic Transcriptional Signatures to Generate Maps of Divergent Cellular States. Cell Syst 5:105-118.e9
Wang, Belinda; Krall, Elsa Beyer; Aguirre, Andrew James et al. (2017) ATXN1L, CIC, and ETS Transcription Factors Modulate Sensitivity to MAPK Pathway Inhibition. Cell Rep 18:1543-1557
Meyers, Robin M; Bryan, Jordan G; McFarland, James M et al. (2017) Computational correction of copy number effect improves specificity of CRISPR-Cas9 essentiality screens in cancer cells. Nat Genet 49:1779-1784
Krall, Elsa B; Wang, Belinda; Munoz, Diana M et al. (2017) KEAP1 loss modulates sensitivity to kinase targeted therapy in lung cancer. Elife 6:
Choudhury, Atish D; Schinzel, Anna C; Cotter, Maura B et al. (2017) Castration Resistance in Prostate Cancer Is Mediated by the Kinase NEK6. Cancer Res 77:753-765
Tsherniak, Aviad; Vazquez, Francisca; Montgomery, Phil G et al. (2017) Defining a Cancer Dependency Map. Cell 170:564-576.e16

Showing the most recent 10 out of 27 publications