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、与石棉接触有关的耐药恶性肿瘤。人类MM患者和这种毁灭性疾病的小鼠模型均显示神经纤维瘤病II型肿瘤抑制基因Nf2的频繁丢失，以及Nf2缺失的MM细胞中Nf2的重新表达抑制其增殖/活力和运动能力，这意味着Nf2 LOS在MM的发病机制中起着基础性作用。以前，我们和其他人已经发现，Nf2基因的蛋白产物Merlin参与了p21激活的蛋白激酶(Pak)和哺乳动物类不育蛋白(MST)信号的调节。这两个STE20K在调节细胞的增殖、存活、黏附、运动、扩散和侵袭性方面发挥着重要作用，−特性与NF2缺陷性MM细胞的恶性表型有关。我们推测，这两条途径对于与NF2缺失相关的多发性骨髓瘤的发生是必不可少的，并且这两条途径都可以用于治疗。我们提出了两个目标。在目标1中，我们将确定Nf2缺失的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。由于我们预计像MM这样的侵袭性癌症将适应并最终避开单一靶向药物，如PAK抑制剂，我们还提议使用一种新开发的技术来在使用抗PAK药物治疗之前和治疗期间全球测量所有蛋白激酶的活性，目的是确定潜在的联合治疗的辅助药物靶点。在目标2中，我们计划描述MST在体内Merlin相关信号和病理中的作用，MST是河马肿瘤抑制通路中的定义元件。通过基于细胞的分析，我们将确定Merlin控制MST活性的机制，重点是我们最近观察到的Merlin缺失会诱导从活性Mst1/Mst1和Mst2/Mst2同源二聚体切换到非活性Mst1/Mst2异源二聚体。我们还将通过将我们的MM小鼠模型与有条件的YAP1缺失株杂交来评估YAP缺失对肿瘤发生和进展的影响，以评估针对MM的河马途径的适宜性。拟议的研究不仅将增加我们对主要致癌信号通路的理解，还可能建立PAK和MST激酶作为治疗这一无法治愈的疾病的合适靶点。

 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.