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

Abstract

Gastric cancer (GC) is a prevalent and devastating disease with poor prognosis. Lack of biomarkers for early detection and effective targeted therapeutics for GC patients represent two major challenges for this disease. Through iTRAQ-LC-MS/MS phosphoproteomics analysis of 14 GC vs. 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 > 1000 phosphoproteins profiled. The DDR1 protein and mRNA levels were found to be upregulated in GC cells concomitant with DDR1 gene amplification. IHC staining of more than 200 clinical samples revealed that DDR1 was overexpressed in 41% and 48% of the intestinal and diffuse type of GC cases, respectively, compared to only 3.5% in normal tissues. Higher DDR1 expression correlated 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 the TEAD-YAP targets transcription. Importantly, DDR1 overexpressed GC cells exhibited high vulnerability to selective DDR1 inhibitors. Our study provides preclinical supports for the application of DDR1 selective inhibitor for DDR1-overexpressed gastric cancer.