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The introduction of imatinib, a selective tyrosine kinase inhibitor (TKI), revolutionized the management of advanced GIST. However, the emergence of drug resistance remains a major clinical challenge, limiting long\u2010term efficacy. Resistance mechanisms are multifactorial, predominantly involving secondary mutations in KIT or PDGFRA that impair TKI binding or stabilize the kinase in an active conformation. Beyond genomic alterations, nonmutational adaptive responses\u2014including dysregulation of noncoding RNAs, metabolic reprogramming, epigenetic modifications, and an immunosuppressive tumor microenvironment\u2014significantly contribute to treatment failure. This review comprehensively analyzes these resistance pathways and discusses the evolution of therapeutic strategies toward precision medicine. Current approaches emphasize molecular subtype\u2010guided first\u2010line therapy, ctDNA\u2010driven sequencing of subsequent lines, and the use of novel TKIs (e.g., avapritinib, ripretinib, bezuclastinib) tailored to specific resistance mutations. Furthermore, we explore emerging modalities such as boron neutron capture therapy (BNCT), which offers a kinase\u2010independent mechanism to target resistant disease, and combination strategies that integrate immunotherapy, epigenetic modulators, and pathway\u2010specific inhibitors. Advances in liquid biopsy and molecular profiling are enabling real\u2010time adaptation of therapy, moving GIST management toward a dynamic, personalized paradigm aimed at overcoming resistance and improving patient outcomes.<\/jats:p>","DOI":"10.1111\/jgh.70306","type":"journal-article","created":{"date-parts":[[2026,2,23]],"date-time":"2026-02-23T00:38:58Z","timestamp":1771807138000},"page":"1191-1203","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["Gastrointestinal Stromal Tumors: Molecular Mechanisms of Drug Resistance and Advances in Therapeutic Strategies"],"prefix":"10.1111","volume":"41","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8273-7836","authenticated-orcid":false,"given":"Ding","family":"Jingnuo","sequence":"first","affiliation":[{"name":"Department of General Medicine Hospital of Chengdu University of Traditional Chinese Medicine  Chengdu Sichuan Province People's Republic of 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