Jonathan A Kelber, Theresa Reno,
Sharmeela Kaushal,
Cristina Metildi,
Tracy Wright,
Konstantin Stoletov,
Jessica M Weems,
Frederick D Park,
Evangeline Mose,
Yingchun Wang,
Robert M Hoffman,
Andrew M Lowy,
Michael Bouvet,
Richard L Klemke
[show abstract]
[hide abstract]
ABSTRACT: Early biomarkers and effective therapeutic strategies are desperately needed to treat pancreatic ductal adenocarcinoma (PDAC), which has a dismal 5-year patient survival rate. Here, we report that the novel tyrosine kinase PEAK1 is upregulated in human malignancies, including human PDACs 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. Surprisingly, blockade of ErbB2 expression increased Src-dependent PEAK1 expression, PEAK1-dependent Src activation, and tumor growth in vivo, suggesting a mechanism for the observed resistance of patients with PDACs to therapeutic intervention. Importantly, PEAK1 inactivation sensitized PDAC cells to trastuzumab and gemcitabine therapy. Our findings, therefore, suggest that PEAK1 is a novel biomarker, critical signaling hub, and new therapeutic target in PDACs.
Cancer Research 05/2012; 72(10):2554-64. · 7.86 Impact Factor
