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However, tumors almost inevitably relapse owing to the development of acquired resistance. Resistance mechanisms include secondary ALK mutations and the activation of bypass pathways, such as cMET, cKIT, or EGFR, though some remain unknown. In this study, we analyzed alectinib\u2010resistant patient samples and identified a significant increase in AXL expression in the tumor, and a high level of GAS6, the ligand for AXL, in the pleural effusion. AXL\u2010overexpressing H3122 ALK\u2010rearranged NSCLC cells exhibited partial resistance to alectinib, which was enhanced by GAS6 supplementation but could be overcome by the ALK\/AXL inhibitor gilteritinib. Moreover, GAS6\u2010overexpressing NIH3T3 cells and AXL\u2010expressing H3122 cells were subcutaneously injected into the left and right sides of nude mice simultaneously, followed by alectinib treatment. The supply of GAS6 from NIH3T3 may have accelerated tumor relapse under alectinib treatment. However, even without GAS6\u2010overexpressing NIH3T3, AXL\u2010overexpressing H3122 tumor relapsed within 1\u2009month possibly due to increased host mouse Gas6 expression. Single\u2010cell RNA sequencing revealed that specific cancer\u2010associated fibroblasts (CAFs) and a subset of tumor\u2010associated macrophages (TAMs) are the primary sources of Gas6 in the tumor microenvironment (TME). During alectinib treatment, TAMs increased their infiltration into the TME, whereas CAFs altered their expression patterns, substantially upregulating Mmp11. These findings suggest that AXL expression in resistant cancer cells, combined with increased Gas6 production in the TME, contributes to enhanced ALK\u2010TKI resistance.<\/jats:p>","DOI":"10.1111\/cas.70006","type":"journal-article","created":{"date-parts":[[2025,2,5]],"date-time":"2025-02-05T00:39:06Z","timestamp":1738715946000},"page":"1034-1047","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["AXL\u2010Mediated Drug Resistance in ALK\u2010Rearranged NSCLC Enhanced by GAS6 From Macrophages and MMP11 Positive Fibroblasts"],"prefix":"10.1111","volume":"116","author":[{"given":"Takahiro","family":"Utsumi","sequence":"first","affiliation":[{"name":"Division of Experimental Chemotherapy, Cancer Chemotherapy Center Japanese Foundation for Cancer Research  Tokyo Japan"},{"name":"Department of Respiratory Medicine, Graduate School of Medical Sciences Kyushu University  Fukuoka 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