The role of PCDH7 in lung cancer pathogenesis

项目总结 非小细胞肺癌(NSCLC)是最常见的肺癌形式，也是导致 全球与癌症相关的死亡人数。鉴于目前治疗方案的有效性有限，有一种 迫切需要开发新的和创新的方法，以确定可操作的治疗目标 治疗非小细胞肺癌。我们在基因转座子突变筛选中鉴定了原钙粘附素7(PCDH7) 促进人支气管上皮细胞(HBECs)转化的物质。事实上，Protocadherin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 PCDH7在肺癌中经常过表达，在人类中也有高表达 肿瘤与非小细胞肺癌患者的生存不良密切相关。我们的数据表明PCDH7 过表达可有效增强KRAS和EGFR诱导的MAPK信号转导和肿瘤发生。损失 PCDH7在体外使KRAS突变的NSCLC细胞对MEK抑制剂敏感，并在体内抑制肿瘤形成。这个 本申请的总体目标是利用小鼠确定PCDH7在非小细胞肺癌中的致癌活性 模型和人类细胞，评估PCDH7作为治疗靶点，并确定其分子机制 这种细胞表面蛋白通过它促进肺肿瘤的发生。我们建议阐明这一点的作用 通过检验以下中心假设推测肺癌驱动基因：PCDH7促进KRAS-和 EGFR通过形成SET/PP2A抑制复合体增强MAPK-1而导致肺肿瘤的发生 ERK信号。为了验证这一假设，我们将追求三个具体目标：在目标1中，我们将 研究PCDH7在多大程度上加速突变的KRAS和EGFR介导的肿瘤形成 有条件的PCDH7转基因小鼠模型，并在KrasLSL中使用体细胞基因组编辑抑制PCDH7- G12D；TP53 fl/fl小鼠。在目标2中，我们将阐明SET和PP2A在PCDH7诱导的MAPK信号转导中的作用 和肿瘤的发生。最后，在目标3中，我们将检查PCDH7抑制增强的程度 体外和自体小鼠模型中非小细胞肺癌细胞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来评估PCDH7作为一种治疗方法 靶点，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的发病机制和机制产生新的见解 为追求这种细胞表面受体作为KRAS和EGFR的治疗靶点提供了新的机会 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.