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

描述（由申请人提供）：尽管做出了许多努力，但仍没有克服乳腺癌内分泌耐药性的有效疗法。主要缺点是大多数已知的致癌基因不能与有效和安全的药物相匹配;对于少数抑制剂，由于逃逸途径的快速发展，临床反应是有限和短暂的。因此，关键是要发现未知生存途径中缺失的靶标和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标。这项分析揭示了一个新的靶点，Nemo样激酶（NLK），它在约30%的乳腺癌中扩增和/或过表达。我们已经表明，NLK驱动更积极的表型，赋予内分泌抵抗性生长，并预测他莫昔芬治疗的患者更差的结果。进一步的研究表明，NLK调节雌激素受体（ER）通路中的多个关键分子或参与内分泌抵抗，如STAT 3、FOXO、AKT、ERK和p27。更重要的是，已经鉴定出一种有效的NLK抑制剂，其有效地使乳腺癌细胞对他莫昔芬敏感。NLK可以被多种生长因子激活，这些生长因子与众所周知的乳腺癌途径不同。因此，我们假设，这种蛋白质可能是一个枢纽分子，驱动以前未知的生存信号在相当大的一部分难治性乳腺肿瘤。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。提出以下研究来检验该假设：目的1将研究NLK如何与ER通路交叉以恢复ER活性，以及NLK如何参与ER非依赖性信号传导以在内分泌治疗的背景下提供替代生存和侵入性刺激。目的2：利用移植的NLK诱导的基因扰动模型，建立NLK在肿瘤形成和激素抵抗中的作用。将在携带NLK-高ER+异种移植乳腺肿瘤的小鼠中评估NLK抑制剂在致敏内分泌治疗中的治疗价值。目的3探讨NLK蛋白与乳腺癌患者接受他莫昔芬或芳香化酶抑制剂治疗的疗效或复发的相关性。本研究还将建立NLK免疫组织化学（IHC）试验，以选择NLK靶向治疗的患者。 我们期望这些研究将证实NLK在乳腺癌内分泌耐药性中的作用，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抑制剂在乳腺癌内分泌治疗中的作用机制。 NLK IHC作为精准医学的预测性检测。这种个体化的靶向治疗将使相当多的已经发展或可能发展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.