The role of PCDH7 in lung cancer pathogenesis

项目摘要 非小细胞肺癌（NSCLC）是肺癌的最常见形式，并且是肺癌的主要原因。 全球癌症相关死亡人数。鉴于目前治疗方案的有效性有限， 迫切需要开发新的创新方法，以确定可行的治疗靶点， 治疗NSCLC。我们在转座子诱变筛选基因中鉴定了原钙粘蛋白7（PCDH 7 其促进人支气管上皮细胞（HBEC）的转化。事实上，原钙粘蛋白家族 成员代表了一类在癌症中具有重要功能的新兴分子。我们发现， PCDH 7在肺癌中高表达，PCDH 7蛋白在人肺癌中高表达 肿瘤与NSCLC患者的低生存率密切相关。我们的数据表明，PCDH 7 过表达有力地增强KRAS和EGFR诱导的MAPK信号传导和肿瘤发生。损失 PCDH 7在体外使KRAS突变型NSCLC细胞对MEK抑制剂敏感，并在体内抑制肿瘤发生。的 本申请的总体目标是使用小鼠来确定PCDH 7在NSCLC中的致癌活性 模型和人类细胞，评估PCDH 7作为治疗靶点，并确定分子机制 通过该细胞表面蛋白促进肺肿瘤发生。我们建议阐明这一作用 通过测试以下中心假设，我们可以确定一个假定的肺癌驱动基因：PCDH 7促进KRAS-和 EGFR通过形成SET/PP 2A抑制复合物促进MAPK-1介导的肺肿瘤发生 ERK信号传导。为了检验这一假设，我们将追求三个具体目标：在目标1中，我们将 使用以下方法表征PCDH 7加速突变型KRAS和EGFR介导的肿瘤发生的程度： 条件性PCDH 7转基因小鼠模型，并在KrasLSL中使用体细胞基因组编辑抑制PCDH 7- G12 D; Tp 53 fl/fl小鼠。目的2：阐明SET和PP 2A在PCDH 7诱导的MAPK信号转导中的作用 和肿瘤发生。最后，在目标3中，我们将检查PCDH 7抑制增强 在体外NSCLC细胞和本地小鼠模型中对临床批准的抑制剂的敏感性。这些 aims将利用我们和我们合作者的专业知识，评估PCDH 7作为治疗药物的价值。 靶向，并确定这种细胞表面蛋白促进肺肿瘤发生的机制。我们 预计这些研究将对肺癌发病机制产生新的见解， 提供了新的机会，追求这种细胞表面受体作为治疗靶点，在KRAS-和EGFR- 导致肺癌。

PROJECT SUMMARY Non-small cell lung cancer (NSCLC) is the most common form of lung cancer and is the leading cause of cancer-associated deaths worldwide. Given the limited effectiveness of current treatment regimes, there is a critical need for the development of new and innovative approaches to identify actionable therapeutic targets to treat NSCLC. We identified PROTOCADHERIN 7 (PCDH7) in a transposon mutagenesis screen for genes that promote transformation of human bronchial epithelial cells (HBECs). Indeed, Protocadherin family members represent an emerging class of molecules with important functions in cancer. We found that that PCDH7 is frequently overexpressed in lung cancer and that high expression of PCDH7 protein in human tumors strongly associates with poor survival of NSCLC patients. Our data demonstrate that PCDH7 overexpression potently enhances KRAS- and EGFR-induced MAPK signaling and tumorigenesis. Loss of PCDH7 sensitizes KRAS-mutant NSCLC cells to MEK inhibitors in vitro, and inhibits tumorigenesis in vivo. The overall objectives of this application are to define the oncogenic activity of PCDH7 in NSCLC using mouse models and human cells, evaluate PCDH7 as a therapeutic target, and identify the molecular mechanisms through which this cell surface protein promotes lung tumorigenesis. We propose to elucidate the role of this putative lung cancer driver gene by testing the following central hypothesis: PCDH7 promotes KRAS-and EGFR-driven lung tumorigenesis by forming a SET/PP2A inhibitory complex that potentiates MAPK- ERK signaling. Three Specific Aims will be pursued in order to test this hypothesis: In Aim 1, we will characterize the extent to which PCDH7 accelerates mutant KRAS- and EGFR-mediated tumorigenesis using a conditional PCDH7 transgenic mouse model, and inhibit PCDH7 using somatic genome editing in KrasLSL- G12D; Tp53 fl/fl mice. In Aim 2, we will elucidate the roles of SET and PP2A in PCDH7-induced MAPK signaling and tumorigenesis. Finally, in Aim 3, we will examine the extent to which PCDH7 inhibition enhances sensitivity to clinically approved inhibitors in NSCLC cells in vitro and in autochthonous mouse models. These aims will take advantage of our expertise, and that of our collaborators, to evaluate PCDH7 as a therapeutic target, and identify the mechanisms through which this cell surface protein promotes lung tumorigenesis. We anticipate that these studies will yield novel insights into the mechanisms of lung cancer pathogenesis and provide new opportunities to pursue this cell surface receptor as a therapeutic target in KRAS- and EGFR- driven lung cancers.