00085472can113552-sup-f5_3076k.pdf (3 MB)
Supplementary Figure 5 from KRas Induces a Src/PEAK1/ErbB2 Kinase Amplification Loop That Drives Metastatic Growth and Therapy Resistance in Pancreatic Cancer
journal contributionposted on 2023-03-30, 20:49 authored by 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
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ARTICLE ABSTRACTEarly 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 Res; 72(10); 2554–64. ©2012 AACR.
BiomarkersMetastasis biomarkersCarcinogenesisPremalignancySignal transductionTumor initiation and promotionDrug MechanismsCellular responses to anticancer drugsDrug ResistanceNovel mechanismsRegulation of gene expression in drug resistanceDrug TargetsGastrointestinal CancersPancreatic cancerProgression, Invasion & MetastasisMetastasisTumor progression