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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\n                    <jats:italic>FGFR2<\/jats:italic>\n                    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\n                    <jats:italic>FGFR2<\/jats:italic>\n                    -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-\u03b3 secretion of CD8\n                    <jats:sup>+<\/jats:sup>\n                    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\n                    <jats:italic>FGFR2<\/jats:italic>\n                    -amplified GC.\n                  <\/jats:p>","DOI":"10.7554\/elife.104060","type":"journal-article","created":{"date-parts":[[2025,1,16]],"date-time":"2025-01-16T11:25:27Z","timestamp":1737026727000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.104060","source":"Crossref","is-referenced-by-count":0,"title":["Blocking SHP2 benefits FGFR2 inhibitor and overcomes its resistance in FGFR2-amplified gastric cancer"],"prefix":"10.7554","volume":"14","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-3041-6300","authenticated-orcid":true,"given":"Yue","family":"Zhang","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/01rxvg760","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Oncology, Nanjing Drum Tower Hospital, Affiliated Hospital of 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