{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T16:13:34Z","timestamp":1759767214219,"version":"build-2065373602"},"reference-count":96,"publisher":"MDPI AG","issue":"10","license":[{"start":{"date-parts":[[2025,10,5]],"date-time":"2025-10-05T00:00:00Z","timestamp":1759622400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["www.mdpi.com"],"crossmark-restriction":true},"short-container-title":["CIMB"],"abstract":"<jats:p>Introduction: Gastrointestinal stromal tumors (GISTs) are primarily driven by mutations in KIT (KIT proto-oncogene receptor tyrosine kinase) or PDGFRA (platelet-derived growth factor receptor alpha), but resistance to tyrosine kinase inhibitors (TKIs) such as imatinib remains a major clinical challenge. Alterations in fibroblast growth factor receptor 2 (FGFR2), although rare, are emerging as important contributors to tumor progression and drug resistance. This review evaluates the molecular mechanisms, expression profiles, detection methods, and therapeutic implications of FGFR2 in GIST. Methods: We searched PubMed, Web of Science, Google Scholar, and ClinicalTrials.gov for studies published between January 2010 and June 2025, using combinations of keywords related to FGFR2, gastrointestinal stromal tumor, resistance mechanisms, gene fusion, amplification, polymorphisms, and targeted therapy. Eligible studies were critically assessed to distinguish GIST-specific data from evidence extrapolated from other cancers. Results:FGFR2 is expressed in multiple normal tissues and at variable levels in mesenchymal-derived tumors, including GIST. Its alterations occur in approximately 1\u20132% of GIST cases, most commonly as gene fusions (e.g., FGFR2::TACC2, &lt;1%) or amplifications (1\u20132%); point mutations and clinically significant polymorphisms are extremely rare. These alterations activate the MAPK\/ERK and PI3K\/AKT pathways, contribute to bypass signaling, and enhance DNA damage repair, thereby promoting TKI resistance. Beyond mutations, mechanisms such as amplification, ligand overexpression, and microenvironmental interactions also play roles. FGFR2 alterations appear mutually exclusive with KIT\/PDGFRA mutations but occasional co-occurrence has been reported. Current clinical evidence is largely limited to small cohorts, basket trials, or case reports. Conclusions:FGFR2 is an emerging oncogenic driver and biomarker of resistance in a rare subset of GISTs. Although direct evidence remains limited, particularly regarding DNA repair and polymorphisms, FGFR2-targeted therapies (e.g., erdafitinib, pemigatinib) show potential, especially in combination with TKIs or DNA-damaging agents. Future research should prioritize GIST-specific clinical trials, the development of FGFR2-driven models, and standardized molecular diagnostics to validate FGFR2 as a therapeutic target.<\/jats:p>","DOI":"10.3390\/cimb47100822","type":"journal-article","created":{"date-parts":[[2025,10,6]],"date-time":"2025-10-06T15:05:06Z","timestamp":1759763106000},"page":"822","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Molecular Mechanisms and Clinical Implications of Fibroblast Growth Factor Receptor 2 Signaling in Gastrointestinal Stromal Tumors"],"prefix":"10.3390","volume":"47","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-7042-6023","authenticated-orcid":false,"given":"Yanyun","family":"Hong","sequence":"first","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang University School of Medicine, 57, Qingchun Road, Hangzhou 310016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Xiaodong","family":"Wang","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang University School of Medicine, 57, Qingchun Road, Hangzhou 310016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Chunhui","family":"Shou","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang University School of Medicine, 57, Qingchun Road, Hangzhou 310016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3365-2155","authenticated-orcid":false,"given":"Xiaosun","family":"Liu","sequence":"additional","affiliation":[{"name":"The First Affiliated Hospital, Zhejiang University School of Medicine, 57, Qingchun Road, Hangzhou 310016, China"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,10,5]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"821","DOI":"10.1002\/cncr.20862","article-title":"Gastrointestinal stromal tumors: The incidence, prevalence, clinical course, and prognostication in the preimatinib mesylate era-A population-based study in western Sweden","volume":"103","author":"Nilsson","year":"2005","journal-title":"Cancer"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1097\/CCO.0b013e3281338885","article-title":"Second line therapies for the treatment of gastrointestinal stromal tumor","volume":"19","author":"Joensuu","year":"2007","journal-title":"Curr. 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