The Role of Aurora Kinase in Upper Gastrointestinal Adenocarcinomas

描述（由申请人提供）：食管和胃的上消化道腺癌（UGC）是世界范围内的主要健康问题。在美国，大约80%的患者存在区域或远处转移。不幸的是，UGC的死亡率接近发病率，这表明可用的治疗选择是有限的和无效的。了解UGC的分子生物学和信号网络是开发可能改善结果的特定疗法的关键一步。这个建议源于我们最初的发现，极光激酶A（AURKA）是一个关键的目标，在20 q扩增子，在大约60%的UGC过表达。我们最近的研究表明，AURKA蛋白是一种有效的促生存蛋白，通过激活致癌信号通路促进对化疗药物的耐药性。我们的初步数据表明AURKA介导EIF 4 E的上调和磷酸化。我们还表明，与其亲本细胞相比，对mTOR抑制剂RAD 001具有获得性抗性的细胞产生AURKA蛋白水平的增加，而AURKA的过表达导致对mTOR抑制剂RAD 001的抗性。最近的几项研究表明，EIF 4 E是几种癌基因如c-MYC、CCND 1和VEGF的帽依赖性翻译的关键组分。我们已经发现了AURKA-EIF 4 E-MYC的一个新的正反馈环的存在，该环驱动癌细胞存活和对治疗的抗性。此外，我们的数据提供的证据表明，AURKA可以绕过关键的信号通路和磷酸化EIF 4 E独立的mTOR，AKT和ERK 1/2的活动。基于我们的新发现，我们假设AURKA-EIF 4 E-MYC信号环的激活和EIF 4 E依赖性致癌翻译驱动癌细胞存活以及对RAD 001的抗性。在目的1中，我们将研究AURKA在调节UGC中EIF 4 E帽依赖性翻译中的作用。我们将研究Aim 2中AURKA-EIF 4 E-MYC环的机制和分子功能。本提案的目的3将确定AURKA-EIF 4 E-MYC轴的潜在临床意义。为此，我们还将研究使用AURKA抑制剂MLN 8237单独或组合靶向AURKA-EIF 4 E-MYC轴以克服对RAD 001的耐药性的治疗潜力。在我们的工作完成后，我们希望揭示一个新的范式，通过AURKA-EIF 4 E-MYC轴调节癌细胞存活的分子机制。该项目的翻译部分已经建立了可测量的终点，可以促进更好的诊断，预后和可能的治疗干预措施的发展。因此，我们的研究结果将对理解生物学产生积极影响，这可能会加速致命UGC的新型医学治疗的发展。

DESCRIPTION (provided by applicant): Upper gastrointestinal adenocarcinomas (UGCs) of the esophagus and stomach are a major health problem world-wide. Approximately 80% of patients in the United States present with regional or distant metastases. Unfortunately, the mortality rates for UGCs approach incidence rates, suggesting that the available therapeutic options are limited and ineffective. Understanding the molecular biology and signaling networks of UGCs is a critical step in order to develop specific therapies that can potentially improve the outcomes. This proposal stems from our original finding that Aurora kinase A (AURKA) is a critical target at the 20q amplicon that is overexpressed in approximately 60% of UGCs. Our recent studies indicate that the AURKA protein is a potent pro-survival protein that promotes resistance to chemotherapeutic drugs through activation of oncogenic signaling pathways. Our preliminary data demonstrate that AURKA mediates up- regulation and phosphorylation of EIF4E. We have also shown that cells with acquired resistance to mTOR inhibitor RAD001 develop an increase in the protein level of AURKA, as compared to their parental cells, whereas overexpression of AURKA leads to resistance to mTOR inhibitor RAD001. Several recent studies have shown that EIF4E is a key component of cap-dependent translation of several oncogenes such as c- MYC, CCND1, and VEGF. We have uncovered the presence of a novel positive feedback loop of AURKA- EIF4E-MYC that drives cancer cell survival and resistance to therapy. In addition, our data provide evidence that AURKA can bypass key signaling pathways and phosphorylate EIF4E independent of mTOR, AKT and ERK1/2 activities. Based on our novel discoveries, we hypothesize that activation of the AURKA-EIF4E-MYC signaling loop and EIF4E-dependent oncogenic translation drive cancer cell survival as well as resistance to RAD001. In Aim 1, we will investigate the role of AURKA in regulating EIF4E cap-dependent translation in UGCs. We will investigate the mechanisms and molecular functions of the AURKA-EIF4E-MYC loop in Aim 2. Aim 3 of this proposal will determine the potential clinical significance of the AURKA-EIF4E-MYC axis. In this aim, we will also investigate the therapeutic potential of targeting the AURKA-EIF4E-MYC axis using AURKA inhibitor MLN8237 alone or in combinations for overcoming resistance to RAD001. Upon completion of our work, we expect to unveil a new paradigm for molecular mechanisms regulating cancer cell survival by AURKA-EIF4E-MYC axis. The translational components of this project have been established with measurable end points that could facilitate the development of better diagnostic, prognostic, and possibly therapeutic interventions. Therefore, our findings will have a positive impact on understanding the biology which could accelerate the development of novel medical treatments for the deadly UGCs.