Intercepting novel functions of AURKA in gastric tumorigenesis

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ABSTRACT/SUMMARY Gastric carcinoma (GAC) is the third most common cause of cancer-related death world-wide, causing more than 700,000 deaths each year. Unfortunately, the majority of gastric cancer patients are diagnosed at a late stage (Stage III or IV) in the United States, with a poor response to therapy and five-year survival rate of 5.2%. Infection with Helicobacter pylori (H. pylori), a type I carcinogen, is the main risk factor for gastric carcinogenesis. Infection with H. pylori creates a unique environment where epithelial cells must adapt to chronic cellular stress and are forced develop adaptive survival fitness properties that not only promote tumorigenesis but also resistance to chemotherapeutics. Understanding the molecular functions of carcinogenic biological factors such as H. pylori infection is a key step for developing evidence-based therapeutic approaches that are founded on the biology and molecular underpinning of gastric carcinogenesis. We have found that Aurora kinase A (AURKA) is a critical target at the 20q amplicon, overexpressed in approximately 60% of gastric cancers. We identified novel functions of AURKA in promoting EIF4E and cap- dependent translation of critical genes such as SOX9 and LGR5 that promote survival and expansion of tumorigenic cells in response to infection. We have also found that treatment-resistant cells were enriched for high levels of AURKA, SOX9, and LGR5. This proposal has three specific aims that include mechanistic, functional, and translational studies using unique in vitro and in vivo models, including organoid cultures and mouse models. In aim 1, we will investigate the mechanistic role of AURKA in reprogramming the translational machinery in response to infection with H. pylori. We will determine the AURKA-dependent functions in promoting gastric tumorigenesis and resistance to therapy, using in vivo models in Aim 2. The translational significance of our findings and therapeutic efficacy of targeting AURKA will be investigated in Aim 3. Upon completion of this work, we expect to unveil a new paradigm of cross-talk between AURKA and EIF4E- dependent translational machinery in promoting gastric tumorigenesis and resistance to therapy.