FGFR2 gene amplification in gastric cancer predicts sensitivity to the selective FGFR inhibitor AZD4547
Menée in vitro et in vivo, cette étude évalue l'association entre une amplification du gène FGFR et la réponse à un inhibiteur sélectif de FGFR, notamment le composé appelé AZD4547, pour le traitement de patients atteints d'un cancer gastrique
FGFR gene aberrations are associated with tumor growth and survival. We explored the role of FGFR2 amplification in gastric cancer (GC) and the therapeutic potential of AZD4547, a potent and selective ATP competitive receptor tyrosine kinase inhibitor of FGFR1-3, in patients with FGFR2-amplified GC. Array comparative genomic hybridization and FISH were used to identify FGFR2 amplification in GC patient tumor samples. The effects of FGFR2 modulation were investigated in GC cells with FGFR2 amplification and in patient-derived GC xenograft models using two approaches; inhibition with AZD4547 and shRNA knockdown of FGFR2. Amplification of FGFR2 was identified in a subset of Chinese and Caucasian patients with GC. GC cell lines SNU-16 and KATOIII, carrying the amplified FGFR2 gene, were extremely sensitive to AZD4547 in vitro with GI50 values of 3nM and 5nM, respectively. AZD4547 effectively inhibited phosphorylation of FGFR2 and its downstream signaling molecules and induced apoptosis in SNU-16 cells. Furthermore, inhibition of FGFR2 signaling by AZD4547 resulted in significant dose-dependent tumor growth inhibition in FGFR2-amplified xenograft (SNU-16) and PDGCX models (SGC083), but not in non-amplified models. ShRNA knockdown of FGFR2 similarly inhibited tumor growth in vitro and in vivo. Finally, compared to monotherapy, we demonstrated enhancement of in vivo antitumor efficacy using AZD4547 in combination with chemotherapeutic agents. FGFR2 pathway activation is required for driving growth and survival of GC carrying FGFR2 gene amplification both in vitro and in vivo. Our data support therapeutic intervention with FGFR inhibitors, such as AZD4547, in patients with GC carrying FGFR2 gene amplification.
Clinical Cancer Research , résumé, 2013