IKK/NF-kappaB Signaling in Cancer: Therapy, Resistance, and Tumor Initiating Cells

 描述(申请人提供)：IKK/NF-B通路在癌症的发生和发展中显然很重要，但我们还不完全了解该通路促进肿瘤表型的机制，临床上也没有特定的抑制物。最近的研究发现，典型的和非典型的NF-B都有助于癌症的进展，这增加了癌症中相对于NF-B的复杂性，但许多研究只关注典型的途径，然后得出结论，NF-B在特定的癌症中很重要，但不是绝对关键的。此外，结果表明IKK具有与其调节NF-B的能力分开的关键信号功能，这增加了复杂性；例如，我们发现IKK控制自噬和mTORC1信号，这两个信号在许多癌症中都很重要-但被认为是相互拮抗的。最近，我们和其他人确定了IKK/NF-B信号在促进三阴性乳腺癌启动细胞表型中的作用，证据表明典型的和非典型的IKK/NF-B都是重要的。此外，前列腺癌和胶质瘤的初步数据显示，IKK/NF-B信号对肿瘤细胞癌的表型至关重要。在所有这些研究中，核因子-B的活性在TIC间隔区被增强/改变，尽管解释这一现象的机制尚不清楚。初步数据表明，在PSA低/AR低和PSA高/AR高的前列腺癌细胞中，IKK/NF-B机制不同，并表明IKK可能通过直接磷酸化促进前列腺组织中AR水平的降低。PSA低/AR低的前列腺癌患者对抗AR治疗有抵抗力，这表明前列腺癌的复发是由该细胞室的存活/扩张驱动的。这项提案的目标是：(1)说明以下方面的独特贡献 关于RAS驱动的癌症和乳腺癌的典型和非典型的NF-B，(Ii)确定与癌症中的典型和非典型的NF-B相关的转录输出，(Iii)确定NF-B信号在驱动肿瘤起始细胞表型中的参与-集中在脑、胶质瘤和前列腺癌，以及与IKK通路在促进PSA-LO/AR-LO TIC表型中的参与相关的附加研究，假设这会导致对抗AR治疗的抵抗，(Iv)确定在TICs中促进改变的NF-B反应的信号事件，(V)描述IKK信号网络的特征，将IKK信号与控制癌症中的自噬和mTORC1信号联系起来，假设IKK功能驱动两条通路都被激活，(Vi)确定对IKK抑制剂的耐药机制-侧重于通过剩余的IKK/NF-B信号和动态组重新编程来补偿，以及(Vii)促进抑制物进入临床前和临床环境。

 DESCRIPTION (provided by applicant): 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.