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Chromosomal instability (CIN) is a hallmark of cancer and results in genetic diversity. In this study, we demonstrated by transcriptomic analysis that CIN activates the cGAS\u2013STING signaling pathway, which leads to EGFR-TKI refractoriness in a subset of EGFR-mutated NSCLC patients. Furthermore, EGFR-mutated H1975dnMCAK cells, which frequently underwent chromosomal mis-segregation, demonstrated refractoriness to the EGFR-TKI osimertinib compared to control cells. Second, H1975dnMCAK cells exhibited activation of cGAS\u2013STING signaling and its downstream signaling, including tumor-promoting cytokine IL-6. Finally, chromosomally unstable EGFR-mutated NSCLC exhibited enhanced epithelial\u2013mesenchymal transition (EMT). Blockade of cGAS\u2013STING-TBK1 signaling reversed EMT, resulting in restored susceptibility to EGFR-TKIs in vitro and in vivo. These results suggest that CIN may lead to the activation of cGAS\u2013STING signaling in some EGFR-mutated NSCLC, resulting in EMT-associated EGFR-TKI resistance.<\/jats:p>","DOI":"10.3390\/cells14060447","type":"journal-article","created":{"date-parts":[[2025,3,17]],"date-time":"2025-03-17T08:57:02Z","timestamp":1742201822000},"page":"447","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":9,"title":["Chromosomal Instability Is Associated with cGAS\u2013STING Activation in EGFR-TKI Refractory Non-Small-Cell Lung Cancer"],"prefix":"10.3390","volume":"14","author":[{"given":"Kimio","family":"Yonesaka","sequence":"first","affiliation":[{"name":"Department of Medical Oncology, Kindai University Faculty of Medicine, Osaka 589-8511, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takashi","family":"Kurosaki","sequence":"additional","affiliation":[{"name":"Department of Medical Oncology, Kindai University 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