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 fusion 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 Compared 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.
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