Abstract 4167: KRas induces a Src/PEAK1/ErbB2 kinase amplification loop to drive pancreatic cancer growth, metastasis and therapy resistance

• Published in: Cancer research (Chicago, Ill.) Ill.), 2012-04, Vol.72 (8_Supplement), p.4167-4167
• Main Authors: Kelber, Jonathan A., Reno, Theresa, Kaushal, Sharmeela, Metildi, Cristina, Stoletov, Konstantin, Weems, Jessica, Park, Fred D., Wright, Tracy, Mose, Evangeline, Hoffman, Robert M., Lowy, Andrew M., Bouvet, Michael M., Klemke, Richard L.
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2012-4167

Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. We recently identified PEAK1 (pseudopodium-enriched atypical kinase one, SGK269) as a catalytically active tyrosine kinase that associates with the cytoskeleton and regulates cell migration and proliferation. Tyrosine kinases are highly sought after candidates as biomarkers and therapeutic targets because they induce specific phoshorylation signatures and because their catalytic activity and downstream signals can be inhibited by small molecules. The goal of this current study was to assess the role of PEAK1 expression as a diagnostic/prognostic biomarker and potential therapeutic target in human malignancies. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDAC and pancreatic intraepithelial neoplasia (PanIN). Oncogenic KRas induced a PEAK1-dependent kinase amplification loop between Src, PEAK1 and ErbB2 to drive PDAC tumor growth and metastasis in vivo. Suprisingly, blockade of ErbB2 increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation and tumor growth in vivo, suggesting a mechanism for the resistance of PDAC to therapeutic intervention. Indeed, PEAK1 mediates multiple therapy resistance phenotypes that present major hurdles in the clinical treatment of this disease. Thus, PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDAC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 4167. doi:1538-7445.AM2012-4167