Abstract
BackgroundTargeted therapies are emerging treatment options for gastric cancer (GC). Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. This study aimed to establish PDX GC models, and explore therapeutics targeting Her2, MET(cMet), and FGFR2, which may assist doctor to select the proper target therapy for selected patients.MethodsGC tissues from 32 patients were collected and implanted into immuno-deficient mice. Using immunohistochemistry(IHC) and fluorescent in-situ hybridization (FISH), protein levels and/or gene amplification of Her2, cMet and FGFR2 in those tissues were assessed. Finally, anti-tumor efficacy was tested in the PDX models using targeted inhibitors.ResultsA total of 9 passable PDX models were successfully established from 32 gastric cancer xenograft donors, consisting of HER2,cMet and FGFR2 alterations with percentages of 4(12.5%), 8(25.0%) and 1(3.1%) respectively. Crizotinib and AZD4547 exerted marked antitumor effects exclusively in PDX models with cMet (G30,G31) and FGFR2(G03) amplification. Interestingly, synergistic antitumor activity was observed in G03 (FGFR2-amplifed and cMet non-amplified but IHC [2+]) with simultaneous treatment with Crizotinib and ADZ4547 at day 30 post-treatment. Further in vitro biochemistry study showed a synergistic inhibition of the MAPK/ERK pathway. HER2,cMet and FGFR2 alterations were found in 17 (10.4%), 32(19.6%) and 6(3.7%) in a group of 163 GC patients, and cMet gene amplification or protein overexpression(IHC 3+) was associated with poor prognosis.ConclusionsThese PDX GC models provide an ideal platform for drug screening and evaluation. GC patients with positive cMet or FGFR2 gene amplification may potentially benefit from cMet or FGFR2 targeted therapies or combined targeted therapy.
Highlights
IntroductionPatient-derived tumor xenograft(PDX) models of gastric cancer (GC) closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing
Targeted therapies are emerging treatment options for gastric cancer (GC)
Over the past decade, targeted therapies have greatly improved the outcomes of patients with certain malignancies, including breast, colorectal, and lung cancer, less progress has been made with regard to gastric cancer [4,5,6,7]
Summary
Patient-derived tumor xenograft(PDX) models of GC closely retain the features of the original clinical cancer, offering a powerful tool for preclinical drug efficacy testing. Over the past decade, targeted therapies have greatly improved the outcomes of patients with certain malignancies, including breast, colorectal, and lung cancer, less progress has been made with regard to gastric cancer [4,5,6,7]. Conventional cell-implanted xenograft models are commonly used for the development of new drugs. Prolonged in vitro culture and possible selection cause cell-implanted xenograft models to lose the original molecular characteristics and heterogeneity of primary tumors, which results in poor prediction of the clinical tumor’s drug response [8]. PDX models are becoming a powerful tool for the study of tumor biology and the evaluation of anticancer drugs
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