Abstract
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. 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. 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. 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.
Highlights
Gastric cancer is the fourth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide [1, 2]
Trastuzumab, a recombinant humanized mAb directed against the human epidermal growth factor receptor 2 (HER2), is the only targeted agent to be approved for the first-line treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma [3]
We propose an in vivo model in which trastuzumab therapy induces the selection of gastric cancers overexpressing fibroblast growth factor receptor 3 (FGFR3), which activates the PI3K/AKT/ mTOR signaling pathway, sustaining, in turn, tumor growth and a more aggressive epithelial-to-mesenchymal transition (EMT) phenotype
Summary
Gastric cancer is the fourth most commonly diagnosed cancer and the third leading cause of cancer-related death worldwide [1, 2]. Trastuzumab, a recombinant humanized mAb directed against the human epidermal growth factor receptor 2 (HER2), is the only targeted agent to be approved for the first-line treatment of patients with HER2-overexpressing metastatic gastric or gastroesophageal junction adenocarcinoma [3]. After an initial period of clinical benefit, patients almost inevitably progress, as the tumors become refractory to trastuzumab [4]. Several mechanisms involved in acquired resistance to trastuzumab have been described in breast cancer [5], including overexpression of Cyclin E [6], cross-talk between HER2 and other tyrosine kinase receptors [7, 8], or activation of downstream intracellular signal transducers such as SRC [9]. The molecular mechanisms involved in resistance to trastuzumab in gastric cancer remain largely uncharacterized. Integrated SNP array–based copy number and wholeexome sequencing analyses of data from HER2-amplified gastroesophageal adenocarcinoma revealed that more than half of the cases had additional oncogenic alterations at diagnosis that could
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