PURPOSE: The majority of gastric cancer patients who achieve an initial response 
to trastuzumab-based regimens develop resistance within 1 year of treatment. 
This study was aimed at identifying the molecular mechanisms responsible for 
resistance.
EXPERIMENTAL DESIGN: A HER2+-trastuzumab sensitive NCI-N87 gastric cancer 
orthotopic nude mouse model was treated with trastuzumab until resistance 
emerged. Differentially expressed transcripts between trastuzumab-resistant and 
sensitive gastric cancer cell lines were annotated for functional 
interrelatedness by Ingenuity Pathway Analysis software. Immunohistochemical 
analyses were performed in pretreatment versus posttreatment biopsies from 
gastric cancer patients receiving trastuzumab-based treatments. All statistical 
tests were two-sided.
RESULTS: Four NCI-N87 trastuzumab-resistant (N87-TR) cell lines were 
established. Microarray analysis showed HER2 downregulation, induction of 
epithelial-to-mesenchymal transition, and indicated fibroblast growth factor 
receptor 3 (FGFR3) as one of the top upregulated genes in N87-TR cell lines. In 
vitro, N87-TR cell lines demonstrated a higher sensitivity than did 
trastuzumab-sensitive parental cells to the FGFR3 inhibitor dovitinib, which 
reduced expression of pAKT, ZEB1, and cell migration. Oral dovitinib 
significantly (P = 0.0006) reduced tumor burden and prolonged mice survival 
duration in N87-TR mouse models. A higher expression of FGFR3, phosphorylated 
AKT, and ZEB1 were observed in biopsies from patients progressing under 
trastuzumab-based therapies if compared with matched pretreatment biopsies.
CONCLUSIONS: This study identified the FGFR3/AKT axis as an escape pathway 
responsible for trastuzumab resistance in gastric cancer, thus indicating the 
inhibition of FGFR3 as a potential strategy to modulate this resistance. Clin 
Cancer Res; 22(24); 6164-75. ©2016 AACR.