1D228 Attenuates Sorafenib Resistance in Renal Cell Carcinoma Models by Dual Targeting c-Met and AXL.

Sorafenib is widely used to treat metastatic renal cell carcinoma (RCC); however, the acquired drug resistance limits its efficacy and application in clinical practice. 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.