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However, despite their initial effectiveness, resistance to TKIs remains a significant challenge in clinical practice. Understanding the mechanisms underlying TKI resistance is paramount for improving patient outcomes and developing more effective treatment strategies. In this review, we explored various mechanisms contributing to TKI resistance, including on\u2010target mechanisms and off\u2010target mechanisms, as well as changes in the tumor histology and tumor microenvironment (intrinsic mechanisms). Additionally, we summarized current therapeutic approaches aiming at circumventing TKI resistance, including the development of next\u2010generation TKIs and combination therapies. We also discussed emerging strategies such as the use of dual\u2010targeted antibodies and PROteolysis Targeting Chimeras. Furthermore, we explored future directions in TKI\u2010targeted therapy, including the methods for detecting and monitoring drug resistance during treatment, identification of novel targets, exploration of dual\u2010acting kinase inhibitors, application of nanotechnologies in targeted therapy, and so on. Overall, this review provides a comprehensive overview of the challenges and opportunities in TKI\u2010targeted therapy, aiming to advance our understanding of resistance mechanisms and guide the development of more effective therapeutic approaches in cancer treatment.<\/jats:p>","DOI":"10.1002\/mco2.694","type":"journal-article","created":{"date-parts":[[2024,8,24]],"date-time":"2024-08-24T08:45:31Z","timestamp":1724489131000},"source":"Crossref","is-referenced-by-count":89,"title":["Mechanisms of resistance to tyrosine kinase inhibitor\u2010targeted therapy and overcoming strategies"],"prefix":"10.1002","volume":"5","author":[{"given":"Xuejin","family":"Ou","sequence":"first","affiliation":[{"name":"Division of Thoracic Tumor Multimodality Treatment, Cancer Center, West China Hospital Sichuan University  Chengdu China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ge","family":"Gao","sequence":"additional","affiliation":[{"name":"Division of Thoracic Tumor 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