Overexpression of DDR1 contributes to gastric cancer progression via inhibition of Hippo pathway

Gastric cancer (GC) is a prevalent and devastating disease with a poor prognosis. The lack of biomarkers for early detection and effective targeted therapeutics for GC patients represents two major challenges. Through iTRAQ-LC-MS/MS phosphoproteomic analysis of 14 GC and gastric epithelial cell lines, we discovered Discoidin Domain Receptor tyrosine kinase 1 (DDR1) as a top potential drug target out of 40 tyrosine kinases detected along with over 1000 phosphoproteins profiled. The DDR1 protein and mRNA levels were upregulated in GC cells concurrent with DDR1 gene amplification. IHC staining of more than 200 clinical samples revealed that DDR1 was overexpressed in approximately 41% and 48% of the intestinal and diffuse types of GC cases, respectively, compared to only 3.5% in normal tissues. Higher DDR1 expression was associated with poor prognosis. In cellular models, DDR1 overexpression led to accelerated proliferation, invasion, and malignant transformation, putatively via Hippo pathway inhibition and consequent activation of YAP-TEAD target gene expression. Notably, DDR1-overexpressing GC cells exhibited high vulnerability to selective DDR1 inhibitors. The current study provides preclinical support for the application of DDR1-selective inhibitors for DDR1-overexpressing gastric cancer.