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.
Esophageal and gastroesophageal junction adenocarcinomas are increasing at alarming levels. In this proposal, we plan to characterize the molecular function(s) of AURKA, a frequently overexpressed gene, in order to identify its biological, diagnostic, prognostic, and possibly therapeutic significance.
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