Identification and targeting of the signaling pathways underlying lung cancer.

描述（由申请人提供）：肺癌是全球癌症死亡的主要原因，5年生存率<15%，这主要是由于缺乏对晚期疾病的有效治疗。在超过30%的肺腺癌中发现了K-ras基因的激活突变，这表明K-ras突变是肺癌的驱动因素，也是治疗干预的重要靶点。然而，先前直接靶向突变K-ras的尝试几乎没有成功。因此，针对活化的K-Ras信号的替代方法是必要的。我们的长期目标是确定突变k - ras驱动的肿瘤发生所需的效应物，并开发针对这些分子和途径的治疗方法。我们的初步研究以及其他研究人员的最新发现表明，Notch信号通路是非小细胞肺癌（NSCLC）潜在的重要治疗靶点。在哺乳动物中，Notch家族由四种受体（Notch1-4）组成，目前抑制Notch的方法包括使用γ-分泌酶抑制剂（GSIs），其抑制所有四种受体的激活。不幸的是，由于全局Notch抑制导致严重的肠道毒性，GSIs在患者中的使用受到限制。此外，最近的研究表明，不同的Notch受体在肿瘤发生中具有不同且不重叠的功能，并且这些功能依赖于细胞类型和时间。这些发现表明，针对Notch受体及其下游信号通路的抗癌治疗需要针对个体受体进行定制。鉴于先前的研究结果表明Notch1在k- ras诱导的肿瘤发生中是必需的，我们通过将条件诱导的K-rasG12D敲入小鼠模型与Notch1条件敲除小鼠杂交，测试Notch1在体内突变型k- ras驱动的非小细胞肺癌的发展中是否必要。在这些小鼠中，cre介导的重组同时激活K-rasG12D等位基因并使Notch1失活。我们发现Notch1的缺失显著降低了肿瘤起始和总体肿瘤负荷，表明Notch1是k -ras诱导的肺肿瘤发生所必需的。此外，我们的研究表明Notch1通过抑制p53介导的细胞凋亡来促进k -ras驱动的NSCLC。重要的是，这些结果确定了Notch1活性与野生型p53（占所有NSCLC病例的50%）患者预后不良相关的分子基础。基于我们的发现，我们假设Notch1通过其抑制能力是肺肿瘤发生所必需的

DESCRIPTION (provided by applicant): Lung cancer is the leading cause of cancer deaths worldwide, with 5-year survival rates of <15%, and this is largely due to the lack of effective treatments for advanced disease. Activating mutations of the K-ras gene are found in more than 30% of lung adenocarcinoma, indicating that mutant K- ras is a driver of lung cancer and an important target for therapeutic intervention. However, previous attempts to directly target mutant K-ras have met with little success. Thus, alternative approaches to target activated K-Ras signaling are warranted. Our long-term goals are to identify effectors that are required for mutant K-Ras-driven tumorigenesis and to develop therapeutic approaches to targets these molecules and pathways. Our Preliminary Studies, along with recent findings from others, suggest that Notch signaling pathways are potentially important therapeutic targets in non-small cell lung cancer (NSCLC). The Notch family consists of four receptors in mammals (Notch1-4) and current approaches to Notch inhibition involve the use of γ-secretase inhibitors (GSIs), which inhibit the activation of all four receptors. Unfortunately, the use of GSIs in patients is limited due to severe intestinal toxicities that are a result of global Notch inhibition. In additin, recent studies indicate that the different Notch receptors have distinct and non-overlapping functions in tumorigenesis and that these functions are cell type and timing-dependent. These finding suggest that anti-cancer therapies targeting Notch receptors and their downstream signaling pathways need to be tailored to individual receptors. Given previous findings suggesting Notch1 is required for K-ras-induced tumorigenesis, we tested whether Notch1 is necessary for the development of mutant K-ras-driven NSCLC in vivo, by crossing the conditionally inducible K-rasG12D knock-in mouse model with a Notch1 conditional knockout mouse. In these mice, Cre-mediated recombination simultaneously activates the K-rasG12D allele and inactivates Notch1. We find that loss of Notch1 significantly reduced tumor initiation and overall tumor burden, indicating that Notch1 is required for K-ras-induced lung tumorigenesis. Moreover, our studies have shown that Notch1 contributes to K-ras-driven NSCLC by suppressing p53-mediated apoptosis. Importantly, these results identify the molecular basis for the documented correlation between Notch1 activity and poor prognosis in NSCLC patients having wild type p53, which represent 50% of all NSCLC cases. Based on our findings, we hypothesize that Notch1 is required for lung tumorigenesis via its ability to suppress p53, and that targeting Notch1 and/or its downstream effectors will inhibit the development and/or maintenance of NSCLC. The proposed studies will test this hypothesis and define the mechanisms underlying the requirement for Notch1 in K-Ras driven NSCLC. In addition, we will test the role of Notch1 in NSCLC driven by oncogenic events other than K-ras mutation, to determine if Notch1- directed therapies will provide benefit to a broad spectrum of NSCLC patients.