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.
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.
|Choudhury, Atish D; Schinzel, Anna C; Cotter, Maura B et al. (2016) Castration resistance in prostate cancer is mediated by the kinase NEK6. Cancer Res :|
|Aguirre, Andrew J; Meyers, Robin M; Weir, Barbara A et al. (2016) Genomic Copy Number Dictates a Gene-Independent Cell Response to CRISPR/Cas9 Targeting. Cancer Discov 6:914-29|
|Shen, R R; Zhou, A Y; Kim, E et al. (2015) TRAF2 is an NF-*B-activating oncogene in epithelial cancers. Oncogene 34:209-16|
|Moody, S E; Schinzel, A C; Singh, S et al. (2015) PRKACA mediates resistance to HER2-targeted therapy in breast cancer cells and restores anti-apoptotic signaling. Oncogene 34:2061-71|
|Barbie, Thanh U; Alexe, Gabriela; Aref, Amir R et al. (2014) Targeting an IKBKE cytokine network impairs triple-negative breast cancer growth. J Clin Invest 124:5411-23|
|Zhu, Zehua; Aref, Amir R; Cohoon, Travis J et al. (2014) Inhibition of KRAS-driven tumorigenicity by interruption of an autocrine cytokine circuit. Cancer Discov 4:452-65|
|Hagerstrand, Daniel; Tong, Alexander; Schumacher, Steven E et al. (2013) Systematic interrogation of 3q26 identifies TLOC1 and SKIL as cancer drivers. Cancer Discov 3:1044-57|
|Tu, Daqi; Zhu, Zehua; Zhou, Alicia Y et al. (2013) Structure and ubiquitination-dependent activation of TANK-binding kinase 1. Cell Rep 3:747-58|
|Zhou, Alicia Y; Shen, Rhine R; Kim, Eejung et al. (2013) IKKÎµ-mediated tumorigenesis requires K63-linked polyubiquitination by a cIAP1/cIAP2/TRAF2 E3 ubiquitin ligase complex. Cell Rep 3:724-33|
|Serra, Violeta; Eichhorn, Pieter J A; GarcÃa-GarcÃa, Celina et al. (2013) RSK3/4 mediate resistance to PI3K pathway inhibitors in breast cancer. J Clin Invest 123:2551-63|
Showing the most recent 10 out of 17 publications