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The receptor tyrosine kinases c-Met and AXL play important roles in cancer progression and are involved in tyrosine kinase inhibitor-induced drug resistance in cancers, but whether these two receptors also contribute to sorafenib-induced drug resistance in RCC is unclear. In this study, we evaluated our synthesized compound 1D228, a TKI derived from Tepotinib, in sorafenib-resistant RCC models, which demonstrated further inhibition in sorafenib-resistant RCC cells, and induced 25% more reduction in resistant RCC tumor size by 1D228 combined with sorafenib compared with sorafenib monotherapy in animal models. Mechanistically, resistant RCC exhibited elevated phosphorylation of c-Met and AXL, which was effectively suppressed by 1D228. These findings indicated that compound 1D228 sensitized the sorafenib resistance of RCC by dual targeting the c-Met and AXL signaling pathways. This study suggests that 1D228 may represent a promising preclinical therapeutic strategy for RCC patients with sorafenib resistance mediated by c-Met and AXL activation.<\/jats:p>","DOI":"10.3390\/cells15161450","type":"journal-article","created":{"date-parts":[[2026,8,12]],"date-time":"2026-08-12T12:53:48Z","timestamp":1786539228000},"page":"1450","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["1D228 Attenuates Sorafenib Resistance in Renal Cell Carcinoma Models by Dual Targeting c-Met and AXL"],"prefix":"10.3390","volume":"15","author":[{"given":"Hanxu","family":"Qian","sequence":"first","affiliation":[{"name":"Shandong Center of Technology Innovation for Molecular Targeting and Intelligent Diagnosis and Treatment, Shandong Key Lab of Complex Medical Intelligence and Aging, Shandong Medical and Pharmaceutical University, Yantai 264003, 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