Characterization and drug targeting of the PML tumor suppressor in lung cancer

描述（由申请人提供）：非小细胞肺癌（NSCLC）是美国和全球癌症死亡的主要原因。在本应用中，我们将研究早幼粒细胞白血病肿瘤抑制因子（PML）、酪蛋白激酶2 （CK2）和致癌基因K-RAS （onc-K-RAS）在该疾病发病机制中的作用。此外，我们将在肺癌小鼠模型中测试药物抑制CK2是否具有显著的抗肿瘤作用。PML最初被确定为急性早幼粒细胞白血病PML- rar1的一个组成部分，在诱导癌基因诱导的复制性衰老（OIS）、细胞凋亡和新生血管生成等多种肿瘤抑制功能中发挥关键作用。我们已经确定：1。PML在非小细胞肺癌和其他人类肿瘤中经常丢失，这是由于CK2（一种致癌蛋白激酶）的直接磷酸化引发的异常泛素化；2. CK2抑制剂在异种移植物模型中显示PML依赖的抗肿瘤特性3. 在onc-K-Ras启动的小鼠非小细胞肺癌模型中，Pml缺失使OIS反应丧失，导致肿瘤进展。这些观察表明：1。PML抑制不适当的细胞增殖，在体内作为真正的肿瘤抑制因子；2. CK2激酶活性的上调通过一种涉及异常PML泛素化和降解的机制有助于癌症的发生和进展。我们建议，更好地了解控制OIS的细胞网络将有助于开发新的抗癌疗法。例如，确定PML肿瘤抑制活性、蛋白质稳定性和分解代谢的控制机制将为开发新的靶向药物提供框架。因此，CK2抑制剂有望通过恢复癌细胞内PML蛋白水平和诱导OIS反应来发挥抗肿瘤作用。我们将通过确定介导PML肿瘤抑制功能的机制来解决这些假设。此外，我们将在由onc-K-Ras启动的非小细胞肺癌模型中确定PML丢失的功能意义。最后，我们将在非小细胞肺癌小鼠模型中测试CK2特异性抑制剂的体内抗肿瘤特性。这些研究将揭示导致NSCLC肿瘤发生的机制，并将为开发这种毁灭性疾病的新治疗方法提供框架。公共卫生相关性：非小细胞肺癌（NSCLC）是癌症相关死亡的主要原因。迫切需要新的治疗策略。有了这个建议，我们计划通过更好地理解反对癌症形成的分子网络来实现这一目标。我们将描述早幼粒细胞肿瘤抑制因子（PML）在非小细胞肺癌中的抑瘤特性。此外，我们将测试通过抑制酪蛋白激酶2（一种促进NSCLC肿瘤发生的致癌蛋白激酶）来恢复PML蛋白是否能在体内产生抗肿瘤作用。我们将利用细胞系统、忠实的肺癌非小细胞肺癌小鼠模型和一套独特的新药来进行这些实验。这项工作将为开发治疗这种毁灭性疾病的新策略提供框架。

DESCRIPTION (provided by applicant): Non-small cell lung cancer (NSCLC) is a leading cause of cancer death in the US and worldwide. In this application, we will study the contribution of the promyelocytic leukemia tumor suppressor (PML), casein kinase 2 (CK2), and oncogenic K-RAS (onc-K-RAS) to the pathogenesis of this disease. In addition, we will test in mouse models of lung cancer whether pharmacological inhibition of CK2 has a significant anti-tumor effect. PML, initially identified as a component of the PML-RAR1 of acute promyelocytic leukemia, plays a critical role in multiple tumor suppressive functions such as induction of oncogene induced replicative senescence (OIS), apoptosis, and neoangiogenesis. We have determined that: 1. PML is frequently lost in NSCLC and other human tumors due to aberrant ubiquitination triggered by direct phosphorylation by CK2, an oncogenic protein kinase; 2. CK2 inhibitors display PML dependent anti-tumor properties in xenograft models; 3. Pml loss disables the OIS response leading to tumor progression in a mouse NSCLC model initiated by onc-K-Ras. These observations imply that: 1. PML constrains inappropriate cell proliferation, acting as a bona fide tumor suppressor in vivo; 2. upregulation of CK2 kinase activity contributes to cancer initiation and progression through a mechanism that involves aberrant PML ubiquitination and degradation. We propose that a better understanding of the cellular networks controlling OIS will be instrumental for the development of novel anti-cancer therapies. For example, the identification of the mechanisms controlling PML tumor suppressive activity, protein stability and catabolism will provide the framework for the development of novel targeted drugs. In this regards, CK2 inhibitors are expected to exert an anti-tumor effect by restoring PML protein levels within cancer cells and inducing and OIS response. We will address these hypotheses by identifying the mechanisms that mediate PML tumor suppressive function. In addition, we will determine the functional significance of PML loss in a model of non-small cell lung cancer initiated by onc-K-Ras. Finally, we will test the anti-tumor properties of specific inhibitors of CK2 in vivo in mouse models of NSCLC. These studies will shed light on the mechanisms leading to NSCLC tumorigenesis and will provide the framework for the development of novel therapeutic approaches for this devastating disease. PUBLIC HEALTH RELEVANCE: Non-small cell lung cancer (NSCLC) is a leading cause of cancer-related death. Novel therapeutic strategies are urgently needed. With this proposal, we are planning to move toward this goal by gaining a better understanding of the molecular networks that oppose cancer formation. We will characterize the tumor suppressive properties of the promyelocytic tumor suppressor (PML) in NSCLC. In addition, we will test whether PML protein restoration through inhibition of casein kinase 2, an oncogenic protein kinase that contributes to NSCLC tumorigenesis, leads to an antitumor effect in vivo. We will perform these experiments following an integrated strategy that will utilize cellular systems, a faithful mouse model of lung cancer NSCLC and a unique set of novel drugs. This work will provide the framework for the development of a novel strategy for the treatment of this devastating disease.