An FGFR3 Autocrine Loop Sustains Acquired Resistance to Trastuzumab in Gastric Cancer Patients

G. Piro, C. Carbone, Ivana Cataldo, Federica Di Nicolantonio, Simone Giacopuzzi, G. Aprile, F. Simionato, F. Boschi, Marco Zanotto, Maria M. Mina, R. Santoro, valeria merz , Andrea Sbarbati, Giovanni de Manzoni, Aldo Scarpa, Giampolo Tortora, D. Melisi

Research output: Contribution to journalArticlepeer-review

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 HER2þ-trastuzumab sensitive NCIN87
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 trastuzumabsensitive
parental cells to the FGFR3 inhibitor dovitinib, which
reduced expression of pAKT, ZEB1, and cell migration. Oral
dovitinib significantly (P ¼ 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.
Original languageEnglish
JournalClinical Cancer Research
Publication statusPublished - 2016

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