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

描述(申请人提供)：尽管作出了许多努力，但没有有效的治疗方法来克服乳腺癌的内分泌抵抗。主要的缺点是，大多数已知的癌基因无法与有效和安全的药物匹配；对于少数使用抑制剂的患者，由于逃逸途径的快速发展尚不清楚，临床反应有限且短暂。因此，关键是要发现未知生存途径中缺失的目标，以及可以治疗这种疾病的药物。在这项研究中，我们应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-基因概念签名(ConSig)相结合，从复杂的癌症信号网络中识别关键药物靶点。这项分析揭示了一个新的靶点，Nemo样激酶(NLK)，它在大约30%的乳腺癌中被扩增和/或过度表达。我们已经证明，在接受他莫昔芬治疗的患者中，NLK驱动更具侵袭性的表型，赋予内分泌抵抗生长，并预测更糟糕的结果。进一步的研究表明，NLK调节雌激素受体(ER)途径中的多个关键分子或参与内分泌耐药，如STAT3、FOXO、AKT、ERK和p27。更重要的是，已经发现了一种有效的NLK抑制剂，可以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，我们假设这种蛋白可能是一个中枢分子，它驱动以前未被描述的生存信号，在相当一部分难治性乳腺肿瘤中发出信号。由于NLK抑制剂的安全性已经在其他临床试验中得到证实，它具有立即和高潜力改变乳腺癌患者的治疗方式。建议进行以下研究来验证这一假设：目的1将研究NLK如何与ER途径串扰以恢复ER活性，以及NLK如何在内分泌治疗的背景下参与ER非依赖性信号传递以提供替代的生存和侵袭性刺激。目的2利用移植NLK诱导的遗传扰动模型，建立NLK在肿瘤形成和激素抵抗中的作用。NLK抑制剂在增敏内分泌治疗中的治疗价值将在携带NLK高ER+异种移植乳腺肿瘤的小鼠身上进行评估。目的3研究NLK蛋白与三苯氧胺或芳香化酶抑制剂治疗乳腺癌的疗效或复发的相关性。这项研究还将建立NLK免疫组织化学(IHC)分析，以选择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增敏剂的有效性，并建立 NLK-IHC作为预测精准医学的方法。这种个体化的靶向治疗将使相当一部分已经或可能出现内分泌抵抗的乳腺癌患者受益。

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.