The IKK/NF-?B pathway is clearly important in cancer initiation and progression, yet we do not fully understand the mechanisms whereby this pathway promotes the oncogenic phenotype and there are no specific inhibitors in the clinic. Complexity in cancer relative to NF-?B is raised by recent findings that both canonical and non- canonical NF-?B contribute to cancer progression, yet many studies only focus on the canonical pathway and then conclude that NF-?B is important in a particular cancer but not absolutely critical. Additionally, complexity is raised by results demonstrating that IKK has critical signaling functions separate from its ability to regulate NF-?B; for example we have found that IKK controls autophagy and mTORC1 signaling, both important in many cancers - yet thought to be mutually antagonistic. Recently we and others have established a role for IKK/NF-?B signaling in promoting the triple-negative breast cancer tumor initiating cell (TIC) phenotype, with evidence that both canonical and non-canonical IKK/NF-?B are important. Additionally, preliminary data in prostate cancer and glioma shows that IKK/NF-?B signaling is critical for the TIC phenotype. In all of these studies, NF-?B activity is enhanced/ altered in te TIC compartment, although a mechanism to explain this is not known. Preliminary data indicate a divergent IKK/NF-?B mechanism in PSA-low/AR-low and PSA-high/AR- high prostate cancer cells and indicates the involvement of IKK? in promoting reduced AR levels in the prostate TICs, potentially by direct phosphorylation. The PSA-low/AR-low prostate TICs are resistant to anti-AR therapy, suggesting that recurrence of prostate cancer is driven by survival/expansion of this cell compartment. Goals of this proposal are to: (i) characterize distinct contributions of canonical and non-canonical NF-?B on Ras-driven cancer and on breast cancer, (ii) identify transcriptional output related to canonical and non- canonical NF-?B in cancer, (iii) determine the involvement of NF-?B signaling in driving the tumor-initiating cell phenotype - focused on brain, glioma, and prostate cancer, with additional studies related the involvement of the IKK? pathway in promoting the PSA-lo/AR-lo TIC phenotype with the hypothesis that this drives resistance to anti-AR therapies, (iv) determine signaling events that promote an altered NF-?B response in TICs, (v) characterize the IKK signaling network, relating IKK signaling to control of autophagy and mTORC1 signaling in cancers, with the hypothesis that IKK functions drives both pathways to be active, (vi) determine mechanisms of resistance to IKK inhibitors - focused on compensation by remaining IKK/NF-?B signaling, and by kinome reprogramming and (vii) to facilitate movement of inhibitors into pre-clinical and clinical settings.

Public Health Relevance

The goals of this project are to dissect signaling mechanisms whereby IKK and NF-?B (canonical and non- canonical) promote the phenotype of cancer. Additionally, mechanisms whereby IKK, independent of NF-?B, promotes the oncogenic phenotype will be addressed. We will determine the ability of IKK/NF-?B signaling to drive the tumor-initiating cell phenotype, with the hypothesis that targeting IKK/NF-?B will suppress tumor growth and metastasis, and promote sensitivity to a variety of traditional and targeted therapies (including anti-AR therapy in prostate cancer). We will test existing and emerging inhibitors, some that target both canonical and non-canonical IKK/NF-?B, in a variety of animal tumor models and in patient-derived tumors.

National Institute of Health (NIH)
National Cancer Institute (NCI)
Unknown (R35)
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Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Xu, Wanping
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University of North Carolina Chapel Hill
Schools of Medicine
Chapel Hill
United States
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Porrello, Alessandro; Leslie, Patrick L; Harrison, Emily B et al. (2018) Factor XIIIA-expressing inflammatory monocytes promote lung squamous cancer through fibrin cross-linking. Nat Commun 9:1988
Durand, Joel K; Zhang, Qing; Baldwin, Albert S (2018) Roles for the IKK-Related Kinases TBK1 and IKK? in Cancer. Cells 7:
Zhang, Jing; Wu, Tao; Simon, Jeremy et al. (2018) VHL substrate transcription factor ZHX2 as an oncogenic driver in clear cell renal cell carcinoma. Science 361:290-295
Tegowski, Matthew; Fan, Cheng; Baldwin, Albert S (2018) Thioridazine inhibits self-renewal in breast cancer cells via DRD2-dependent STAT3 inhibition, but induces a G1 arrest independent of DRD2. J Biol Chem 293:15977-15990
Thomas, Clémence; Henry, Whitney; Cuiffo, Benjamin G et al. (2017) Pentraxin-3 is a PI3K signaling target that promotes stem cell-like traits in basal-like breast cancers. Sci Signal 10:
Hsia, Hung-Ching; Hutti, Jessica E; Baldwin, Albert S (2017) Cytosolic DNA Promotes Signal Transducer and Activator of Transcription 3 (STAT3) Phosphorylation by TANK-binding Kinase 1 (TBK1) to Restrain STAT3 Activity. J Biol Chem 292:5405-5417
Lawrence, Cortney L; Baldwin, Albert S (2016) Non-Canonical EZH2 Transcriptionally Activates RelB in Triple Negative Breast Cancer. PLoS One 11:e0165005
Dan, Han C; Antonia, Ricardo J; Baldwin, Albert S (2016) PI3K/Akt promotes feedforward mTORC2 activation through IKK?. Oncotarget 7:21064-75
Rinkenbaugh, Amanda L; Cogswell, Patricia C; Calamini, Barbara et al. (2016) IKK/NF-?B signaling contributes to glioblastoma stem cell maintenance. Oncotarget 7:69173-69187
Rinkenbaugh, Amanda L; Baldwin, Albert S (2016) The NF-?B Pathway and Cancer Stem Cells. Cells 5: