Abstract The dismal prognosis of patients diagnosed with pancreatic cancer points to our limited arsenal of effective anticancer therapies. Oncogenic K-RAS pathway activation is commonly detected in pancreatic cancer. These activations confer drug resistance, drive aggressive tumor growth and metastasis, and ultimately contribute to poor clinical outcome. Currently, there is no curative treatments for pancreatic cancers. Thus, early detection, biomarker discovery, and identifying novel means of countervailing hyperactive K-RAS signals are urgently needed. Seven-In-Absentia Homolog (SIAH), E3 ubiquitin ligase, is an essential downstream component of the RAS signal transduction pathway. SIAH is a member of a highly evolutionarily conserved family of RING finger E3 ubiquitin ligases. Our previous immunohistochemistry (IHC) studies have shown SIAH is a tumor-specific biomarker and SIAH expression is progressively increased as pancreatic tumor progresses from pancreatic intraepithelial neoplasia (PanIN) to pancreatic adenocarcinoma (PDCA) at late stages. In this study, we expand our observations by comparing the expression patterns of SIAH and several newly identified SIAH-interacting proteins using Mayo clinic pancreatic cancer SPORE tissue microarrays (TMA) in a hope of identifying new vulnerability and novel prognostic biomarkers in pancreatic cancer. We hypothesized that SIAH and SIAH-interacting proteins may serve as useful biomarkers and will help to assess effectiveness of anticancer treatment, disease progress, predict clinical outcome and patient survival in the clinical settings. Moreover, we are evaluating SIAH's role in the regulation of the SIAH-interacting proteins and validating the potential mechanisms of these dynamic interactions identified in vitro using pancreatic cancer patients TMA. Ultimately, we aim to explore the new cancer vulnerability, develop new therapeutic strategies, and validate novel prognostic biomarkers for pancreatic cancer patients. This study is performed in a double blind control settings and we are currently awaiting the disclosure of the clinical information from the pathologist. Citation Format: Elizaevta Svyatova. Use of SIAH E3 ubiquitin ligase as a biomarker in pancreatic adenocarcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4540.