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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 prominent immunosuppressive molecule. In this study, we identified FGFR2 amplification in 6.2% (10/161) of GC patients 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 (human GC cell lines) and in vivo (mouse xenograft tumor models) 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-γ 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.
Pubmed ID: 41870032
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The National Natural Science Foundation of China (NSFC) is an organization directly affiliated to the State Council for the management of the National Natural Science Fund. # In accordance with the guiding principles, policies and plans for the development of science and technology in China and by adopting the operating mechanisms for the National Natural Science Fund which conform to the socialism market economic system, NSFC supports basic research and some of applied research, identifies and fosters talented researchers in the realm of science and technology, accelerates the progress of science and technology, and promotes the socioeconomic development in China by giving full play the guidance and coordinating role of the National Natural Science Fund from the central government. # NSFC is in charge of the management of the National Natural Science Fund. It compiles and promulgates the annual Guide to Programs for basic research and some of applied research, handles applications of research projects, and organizes peer review and select the best projects to support. It endeavors to create an academic environment conducive to innovation. # NSFC cooperates with the Ministry of Science and Technology to formulate the principles, policies and plans for the development of basic research in China. When entrusted, it provides consultation and undertakes related assignments on major issues for the development of high technology and applied research in China. # NSFC gives help and support to other Chinese foundations in natural sciences. # NSFC establishes contacts with governmental departments in charge of science and technology, science foundations and related academic organizations in other countries and carries out international cooperation and exchange. # NSFC is responsible for the administration, supervision and guidance of the subordinated bodies. # NSFC undertakes other tasks entrusted by the State Council and the State Leading Group for Science and Technology and Education.
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