Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer

Fibroblast growth factor receptor 2 (FGFR2) is an important member of receptor tyrosine kinase (RTK) family. FGFR2 amplification occurs at a high frequency in gastric cancer (GC) and has been proven to be closely associated with poor prognosis and insensitivity to chemotherapy or immunotherapy. Current FGFR2-targeted therapies have limited efficacy. Hence, how to enhance efficacy and reverse resistance are urgent problems clinically. Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2) serves as the shared downstream mediator of all RTKs and a prominence immunosuppressive molecule. In this study, we identified FGFR2 amplification in 6.2% (10/161) of GC samples in our center. Then we showed that dual blocking SHP2 and FGFR2 enhanced the effects of FGFR2 inhibitor (FGFR2i) in FGFR2-amplified GC both in vitro and in vivo via suppressing RAS/ERK and PI3K/AKT pathways. We further showed that it overcame FGFR2i resistance by reversing the feedback activation mediated by other RTKs and continuously suppressing FGFR2-initiated downstream pathways. Notably, SHP2 blockade could suppress PD-1 expression and promoted IFN-{gamma} secretion of CD8+ T cells, enhancing the cytotoxic functions of T cells in tumor immune microenvironment. Overall, our findings suggest that dual blocking SHP2 and FGFR2 is a compelling rationale with both targeted treatment and immune regulation for FGFR2-amplified GC. Impact statementDual blocking SHP2 and FGFR2 can not only promote the targeted tumor-killing effects and overcome FGFR2 inhibitor resistance caused by feedback activation, but also activate T cell-mediated anti-tumor immunity by inhibiting PD-1 pathway in FGFR2-amplified GC. Funding informationThis work was funded by Grants from National Natural Science Foundation of China (82403862, 82403835), Jiangsu Provincial Natural Science Foundation Youth Project (BK20230151, BK20240247), Jiangsu Provincial Major Science and Technology Program (BG2024026), the Wu Jieping Medical Foundation Special Fund for Targeted Cancer Therapy (Youth Research Project) (320.6750.2023-11-30), Jiangsu Provincial Youth Science and Technology Talent Support Project (JSTJ-2025-715) and General Project of Nanjing Health Science and Technology Development Program (YKK24084).