Integrative Consig: NLK as Attractive Drug Target for Intractable Breast Cancer

描述（申请人提供）：尽管做了很多努力，但没有有效的治疗方法来克服乳腺癌内分泌抵抗。主要的缺点是，大多数已知的致癌基因无法与有效和安全的药物相匹配；对于少数使用抑制剂的患者，由于尚未了解逃逸途径的快速发展，临床反应是有限和短暂的。因此，发现未知生存途径中缺失的靶点和能够治疗这种疾病的药物是至关重要的。在这项研究中，我们采用了一种独特的综合分析，通过将基因组/药理学信息与癌症基因概念特征（ConSig）相结合，从复杂的癌症信号网络中识别出关键的药物靶点。该分析揭示了一个新的靶点，nemo样激酶（NLK），在约30%的乳腺癌中被扩增和/或过表达。我们已经证明NLK驱动更具侵略性的表型，赋予内分泌抗性生长，并预测他莫昔芬治疗的患者预后更差。进一步研究表明，NLK可调节雌激素受体（ER）通路或参与内分泌抵抗的多个关键分子，如STAT3、FOXOs、AKT、ERK和p27。更重要的是，已经发现了一种有效的NLK抑制剂，它能有效地使乳腺癌细胞对他莫昔芬敏感。NLK可以被多种不同于众所周知的乳腺癌途径的生长因子激活。因此，我们假设该蛋白可能是在相当一部分难治性乳腺肿瘤中驱动先前未表征的生存信号的中心分子。由于NLK抑制剂的安全性已经在其他临床试验中得到证实，因此它具有立即改变乳腺癌患者护理的巨大潜力。我们提出以下研究来验证这一假设：目的1将研究NLK如何与内质网通路相互作用以恢复内质网活性，以及NLK如何在内分泌治疗的背景下参与内质网非依赖性信号传导以提供替代的生存和侵入性刺激。目的2将利用移植的NLK诱导遗传扰动模型建立NLK在肿瘤形成和激素抗性中的作用。NLK抑制剂在致敏内分泌治疗中的治疗价值将在NLK高ER+异种乳腺肿瘤小鼠上进行评估。目的3将研究NLK蛋白与乳腺癌患者接受他莫昔芬或芳香酶抑制剂治疗的疗效或复发的相关性。本研究还将建立一种NLK免疫组织化学（IHC）测定方法，以选择接受NLK靶向治疗的患者。我们期望这些研究将证实NLK在乳腺癌内分泌抵抗中的作用，阐明NLK驱动的促进癌细胞存活的机制，验证NLK抑制剂作为内分泌治疗的增敏剂，并建立NLK在乳腺癌内分泌抵抗中的作用机制

DESCRIPTION (provided by applicant): Despite many efforts, no effective therapy exists to overcome breast cancer endocrine resistance. The major drawback is that most of the known oncogenes cannot be matched with potent and safe drugs; for the few with inhibitors, clinical responses are limited and transient due to rapid development of escape pathways not yet understood. It is thus critical to uncover both the missing targets in the unknown survival pathways and the drugs that can tackle this disease. In this study, we apply a unique integrative analysis that identifies key drug targets from the complex cancer signaling network by combining genomic/pharmacological information with cancer-gene concept signature (ConSig). This analysis has revealed a new target, Nemo-like kinase (NLK), which is amplified and/or overexpressed in ~30% of breast cancers. We have shown that NLK drives more aggressive phenotypes, endows endocrine-resistant growth, and predicts worse outcome in tamoxifen- treated patients. Further investigation suggests that NLK modulates multiple key molecules in the estrogen receptor (ER) pathway or involved in endocrine resistance, such as STAT3, FOXOs, AKT, ERK, and p27. More important, a potent NLK inhibitor has been identified which effectively sensitizes breast cancer cells to tamoxifen. NLK can be activated by multiple growth factors distinct from the well-known breast cancer pathways. We thus hypothesize that this protein may be a hub molecule that drives previously uncharacterized survival signaling in a considerable subset of intractable breast tumors. As the safety of the NLK inhibitor has already been established in other clinical trials, it holds an immediate and high potential to transform th care of breast cancer patients. The following studies are proposed to test the hypothesis: Aim 1 will investigate how NLK crosstalks with the ER pathway to restore ER activity, and how NLK engages ER-independent signaling to provide alternative survival and invasive stimuli in the context of endocrine therapy. Aim 2 will establish NLK function in tumor formation and hormone resistance using transplanted NLK inducible genetic perturbation models. The therapeutic value of the NLK inhibitor in sensitizing endocrine therapy will be assessed on mice bearing NLK-high ER+ xenograft breast tumors. Aim 3 will investigate the correlation of NLK protein with the response or relapse of breast cancer patients treated with tamoxifen or aromatase inhibitors. This study will also establish an NLK immunohistochemistry (IHC) assay to select patients for NLK-targeted therapy. We expect that these studies will confirm the role of NLK in breast cancer endocrine resistance, elucidate the NLK-driven mechanisms to promote cancer cell survival, validate the NLK inhibitor as a sensitizing agent to endocrine therapy, and establish the NLK IHC as a predictive assay for precision medicine. This individualized targeted-therapy would benefit a considerable population of breast cancer patients that have developed or are likely to develop endocrine resistance.