title: KRas induces a Src/PEAK1/ErbB2 kinase amplification loop that drives metastatic growth and therapy resistance in pancreatic cancer.
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.
authors.affiliation: Department of Pathology, Division of Surgical Oncology, UCSD, La Jolla, CA 92093, USA.
authors.forename: Jonathan A
authors.initials: JA
authors.lastname: Kelber
authors.forename: Theresa
authors.initials: T
authors.lastname: Reno
authors.forename: Sharmeela
authors.initials: S
authors.lastname: Kaushal
authors.forename: Cristina
authors.initials: C
authors.lastname: Metildi
authors.forename: Tracy
authors.initials: T
authors.lastname: Wright
authors.forename: Konstantin
authors.initials: K
authors.lastname: Stoletov
authors.forename: Jessica M
authors.initials: JM
authors.lastname: Weems
authors.forename: Frederick D
authors.initials: FD
authors.lastname: Park
authors.forename: Evangeline
authors.initials: E
authors.lastname: Mose
authors.forename: Yingchun
authors.initials: Y
authors.lastname: Wang
authors.forename: Robert M
authors.initials: RM
authors.lastname: Hoffman
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Lowy
authors.forename: Michael
authors.initials: M
authors.lastname: Bouvet
authors.forename: Richard L
authors.initials: RL
authors.lastname: Klemke
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000032:analysis; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm; D018734:Genes, erbB-2; D011905:Genes, ras; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D008958:Models, Molecular; D009362:Neoplasm Metastasis / Q000235:genetics; D009368:Neoplasm Transplantation; D015688:Oncogene Protein pp60(v-src) / Q000235:genetics*; D010190:Pancreatic Neoplasms / Q000235:genetics*; D011505:Protein-Tyrosine Kinases / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics; D015533:Transcriptional Activation; D015854:Up-Regulation
chemical_list: D014408:Biomarkers, Tumor; C074810:SRC protein, Rous sarcoma virus; C573947:PEAK1 protein, human; D011505:Protein-Tyrosine Kinases; D015688:Oncogene Protein pp60(v-src)