Role of STE20 protein kinases in malignant mesothelioma

 描述（由申请人提供）：恶性间皮瘤（MM）是一种相对常见的、进展迅速的、与石棉暴露相关的耐药恶性肿瘤。人MM患者和这种毁灭性疾病的小鼠模型都显示出神经纤维瘤病II型肿瘤抑制基因Nf 2的频繁丢失，并且Nf 2在Nf 2缺失的MM细胞中的再表达抑制了它们的增殖/活力并抑制了它们的运动性，这意味着Nf 2丢失在MM发病机制中起着重要作用。在此之前，我们和其他人已经暗示Merlin，Nf 2基因的蛋白产物，在p21激活激酶（Pak）和哺乳动物不育二十（Mst）信号的调节。这两种STE 20激酶在调节细胞增殖、存活、粘附、运动性、扩散和侵袭性方面发挥重要作用，这些特性与Nf 2缺陷型MM细胞的恶性表型有关。我们假设这两种途径对于与NF 2丢失相关的MM肿瘤发生是必不可少的，并且这两种途径都可以用于治疗益处。我们提出两个目标。在目标1中，我们将确定Nf 2-null MM小鼠模型对有效的、新开发的临床前Pak小分子抑制剂的反应。由于我们预计侵袭性癌症（如MM）将适应并最终逃避单一靶向药物（如Pak抑制剂），因此我们还建议使用新开发的技术在抗Pak药物治疗之前和期间全面测量所有蛋白激酶的活性，目的是确定联合治疗的潜在次要药物靶标。在目标2中，我们计划描述Mst（Hippo肿瘤抑制途径中的限定元件）在体内Merlin相关信号传导和病理学中的作用。使用基于细胞的测定，我们将确定梅林控制Mst活性的机制，重点是我们最近的观察，即梅林的损失诱导从活性Mst 1/Mst 1和Mst 2/Mst 2同源二聚体转换为非活性Mst 1/Mst 2异源二聚体。我们还将通过将我们的MM小鼠模型与条件性Yap 1-null品系杂交来评估MM中靶向Hippo通路的适用性，以评估雅普缺失对肿瘤发生率和进展的影响。拟议的研究不仅将增加我们对主要致癌信号通路的理解，而且可以建立Pak和Mst激酶作为这种无法治愈的疾病的治疗干预的合适靶点。

 DESCRIPTION (provided by applicant): Malignant Mesothelioma (MM) is a relatively common, rapidly progressive and treatment-resistant malignancy linked to asbestos exposure. Both human MM patients and mouse models of this devastating disease show frequent loss of the neurofibromatosis type II tumor suppressor gene, Nf2, and re-expression of Nf2 in Nf2-null MM cells inhibits their proliferation/viability and restrains their motility, implying that Nf2 los plays a fundamental role in MM pathogenesis. Previously, we and others have implicated Merlin, the protein product of the Nf2 gene, in the regulation of p21-activated kinase (Pak) and mammalian sterile twenty-like (Mst) signaling. These two STE20 kinases play an important role in regulating cell proliferation, survival, adhesion, motility, spreading and invasiveness − properties connected with the malignant phenotype of Nf2-deficient MM cells. We postulate that both pathways are essential for MM tumorigenesis associated with NF2 loss, and that both pathways can be exploited for therapeutic benefit. We propose two aims. In Aim 1 we will determine the response of a Nf2-null MM mouse model to potent, newly developed preclinical Pak small molecule inhibitors. As we expect that aggressive cancers such as MM will adapt and eventually evade single targeted agents such as Pak inhibitors, we also propose to use a newly developed technology to globally measure the activity of all protein kinases prior to and during treatment with anti-Pak agents, with the goal of identifying potential secondary drug targets for combination therapy. In Aim 2 we plan to delineate the role of the Mst, the defining element in the Hippo tumor suppressor pathway, in Merlin- related signaling and pathology in vivo. Using cell-based assays, we will determine the mechanism by which Merlin controls Mst activity, focusing on our recent observation that loss of Merlin induces a switch from active Mst1/Mst1 and Mst2/Mst2 homodimers to inactive Mst1/Mst2 heterodimers. We will also assess the suitability of targeting the Hippo pathway in MM by crossing our MM mouse model into a conditional Yap1-null strain to assess the effects on Yap loss on tumor incidence and progression. The proposed studies will not only increase our understanding of cardinal oncogenic signaling pathways, but could establish Pak and Mst kinases as suitable targets for therapeutic intervention in this otherwise untreatable disease.