Investigating the Role of the Mek5-Erk5 Kinase Module in Small Cell Lung Cancer

 描述（由申请人提供）：小细胞肺癌（SCLC）每年在全球夺去20多万人的生命，目前仍没有有效的治疗方法用于这种致命的疾病。 疾病除了SCLC启动所需的RB和P53肿瘤抑制因子的普遍丢失外，驱动SCLC进展的关键途径仍未确定。我们的长期目标是了解导致SCLC侵袭性行程的分子事件。最近对100多个人类SCLC肿瘤的基因组进行测序的努力已经确定了罕见的致癌突变和一些正在扩增的区域，但这些分析未能揭示可能驱动这种癌症发展的中心致癌途径。最近，出现了非癌基因成瘾的概念，它指出癌症可能需要某些未被突变标记的活性分子途径。因此，活性但未突变的信号转导子（如激酶）可能在癌症的发展中起关键作用，而测序方法尚未发现。使用新的蛋白质组学方法，我们最近获得了第一个视图的活性激酶组的小细胞肺癌。在SCLC中的活性激酶中，Mek 5特别有趣。Mek 5及其下游靶点Erk 5包含一个特征仍然不明确的信号通路;新出现的证据表明，与研究较多的Mek 1/2-Erk 1/2通路类似，Mek 5/Erk 5轴也可能调节细胞存活和循环。Mek 5和Erk 5从未在SCLC细胞中进行过研究，并且对它们在癌症中的作用知之甚少。在这里，我们假设Mek 5/Erk 5模块对SCLC的生长至关重要。我们的初步观察结果支持这一假设，即Mek 5或Erk 5缺陷的SCLC细胞显示严重的生长缺陷和增加的凋亡性细胞死亡。然而，我们缺乏一个完整的理解，在SCLC的发展在有机体的背景下，这个轴的要求，以及如何Mek 5/Erk 5可能执行这些角色。为了研究Mek 5/Erk 5激酶轴在SCLC中的作用，我们将利用患者来源的异种移植物（PDX）和SCLC的基因工程小鼠模型。我们首先提出确定Mek 5/Erk 5轴是否是小鼠体内SCLC启动和进展所必需的。其次，我们将研究Mek 5/Erk 5在小细胞肺癌维持中的作用，使用遗传学和药理学方法。第三，我们将进行结构-功能研究，并使用先进的蛋白质组学研究Erk 5在SCLC细胞中的作用机制。这项研究将描述一种新的非突变的致瘤信号通路在小细胞肺癌的发展。我们希望更好地了解SCLC发展的机制将有助于确定患者治疗的新治疗方法。

 DESCRIPTION (provided by applicant): Small cell lung cancer (SCLC) claims more than 200,000 lives globally every year, and there are still no effective therapies in use for this fatal disease. Besides universal loss of the RB and P53 tumor suppressors required for SCLC initiation, the key pathways driving SCLC progression have still not been identified. Our long-term goal is to understand the molecular events that result in the aggressive itinerary of SCLC. Recent efforts to sequence the genomes of over 100 human SCLC tumors have identified rare oncogenic mutations and some regions undergoing amplification, but these analyses failed to shed light on a central oncogenic pathway that may drive the development of this cancer. Recently, the concept of non-oncogene addiction has emerged, which states that cancers may require certain active molecular pathways that are unmarked by mutations. Therefore, active but non-mutated signaling transductors such as kinases may play crucial roles in the development of cancers while remaining undiscovered by sequencing approaches. Using novel proteomic methodology, we recently obtained a first view of the active kinome of SCLC. Among active kinases in SCLC, Mek5 is particularly intriguing. Mek5 and its downstream target, Erk5, comprise a still poorly characterized signaling pathway; emerging evidence suggests that, similar to the more studied Mek1/2- Erk1/2 pathway, the Mek5/Erk5 axis may also regulate cell survival and cycling. Mek5 and Erk5 have never been studied in SCLC cells and little is still known about their role in cancer in general. Here we hypothesize that the Mek5/Erk5 module is crucial to the growth of SCLC. This hypothesis is supported by our preliminary observations that Mek5- or Erk5-deficient SCLC cells show severe growth deficiencies and increased apoptotic cell death. However, we lack a complete understanding of the requirement for this axis in SCLC development in the organismal context, and of how Mek5/Erk5 may be performing these roles. To investigate the role of the Mek5/Erk5 kinase axis in SCLC, we will utilize patient-derived xenografts (PDXs) and a genetically-engineered mouse model of SCLC. We first propose to determine if the Mek5/Erk5 axis is necessary for SCLC initiation and progression in mice in vivo. Second, we will investigate the role of Mek5/Erk5 in SCLC maintenance using genetic and pharmacological approaches. Third, we will perform structure-function studies and use advanced proteomics to investigate the mechanisms of action of Erk5 in SCLC cells. This study will characterize a novel non-mutated tumorigenic signaling pathway in the development of SCLC. We hope that a better understanding of the mechanisms underlying SCLC development will aid to identify novel therapeutic approaches for patient treatment.