Co-inhibiting SHP2 and FGFR2 to treat FGFR2-fused gastric cancer by regulating RAS/ERK and PI3K/AKT signaling pathways
10.12354/j.issn.1000-8179.2024.20240715
- VernacularTitle:抑制SHP2和FGFR2调控RAS/ERK及PI3K/AKT通路治疗FGFR2融合胃癌
- Author:
Zhang YUE
1
;
Wang YUE
;
Wei YUTAO
;
Yu LIXIA
;
Liu BAORUI
;
Wei JIA
Author Information
1. 南京大学医学院附属鼓楼医院肿瘤科(南京市 210008)
- Keywords:
gastric cancer;
targeted therapy;
gene fusion;
fibroblast growth factor receptor 2(FGFR2);
Src homology region 2-contain-ing protein tyrosine phosphatase 2(SHP2)
- From:
Chinese Journal of Clinical Oncology
2024;51(14):703-709
- CountryChina
- Language:Chinese
-
Abstract:
Objective:In this study,we explored the application prospects and mechanisms of action of co-inhibiting fibroblast growth factor receptor 2(FGFR2)and Src homology region 2-containing protein tyrosine phosphatase 2(SHP2)in gastric cancer with the TACC2-FGFR2 fu-sion gene.Methods:We established human gastric cancer cell lines overexpressing the TACC2-FGFR2 fusion gene(MKN45TACC2-FGFR2 and NUGC4TACC2-FGFR2 cells)or a control lentiviral virus(MKN45NC and NUGC4NC cells).The cells were treated with the FGFR2 inhibitor AZD4547,the SHP2 inhibitor SHP099,or a combination of both.The proliferation and migration of tumor cells were detected using cell counting Kit-8(CCK-8)and scratch assays.After treating MKN45TACC2-FGFR2 and NUGC4TACC2-FGFR2 cells with different formulations for 1 or 48 h,Western blot was used to detect variations in the levels of FGFR2,SHP2,and proteins downstream of the RAS/ERK and PI3K/AKT signaling pathways.Results:Com-pared to monotherapy,the combination of AZD4547 and SHP099 significantly inhibited the proliferation and migration of MKN45TACC2-FGFFR2 and NUGC4TACC2-FGFFR2 cells.After 1 h of treatment,the combination therapy inhibited the RAS/ERK and PI3K/AKT pathways in MKN45TACC2-FGFFR2 cells to a greater extent than the AZD4547 monotherapy.Forty-eight hours of AZD4547 monotherapy resulted in feedback activation of p-FGFR and p-SHP2,but failed to inhibit the RAS/ERK pathway.However,combination therapy continuously suppressed upstream FGFR2 and SHP2 signaling,as well as downstream RAS/ERK and PI3K/AKT pathways.Conclusions:Co-inhibiting FGFR2 and SHP2 further inhibit gastric cancer with the TACC2-FGFR2 fusion gene by suppressing the RAS/ERK and PI3K/AKT pathways.These findings provide a new treatment mode for patients with gastric cancer with the TACC2-FGFR2 fusion gene.
