An FGFR3 autocrine loop sustains acquired resistance to trastuzumab in gastric cancer patients
Articolo
Data di Pubblicazione:
2016
Abstract:
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 pre- vs. post-treatment 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 pre-treatment 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.
Tipologia CRIS:
03A-Articolo su Rivista
Keywords:
target therapy, drug resistance, gastric cancer, trastuzumab
Elenco autori:
Piro, Geny; Carbone, Carmine; Cataldo, Ivana; Di Nicolantonio, Federica; Giacopuzzi, Simone; Aprile, Giuseppe; Simionato, Francesca; Boschi, Federico; Zanotto, Marco; Mina, Maria Mihaela; Santoro, Raffaela; Merz, Valeria; Sbarbati, Andrea; de Manzoni, Giovanni; Scarpa, Aldo; Tortora, Giampaolo; Melisi, Davide
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