Targeting AXL can effectively overcome c-Met-induced therapeutic resistance in renal cancer and promote tumor cell death through increased oxidative stress

The mechanisms underlying therapeutic resistance to c-Met/receptor tyrosine kinase (RTK) inhibitors in renal cancer remain unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly upregulated. Notably, we found that prolonged treatment with the c-Met/RTK inhibitor, cabozantinib (Cabo), a standard treatment for advanced-stage RCC, markedly increased total c-Met levels and promoted renal cancer cell proliferation. This effect was confirmed not only in vitro but also in murine models and renal tumor tissues from Cabo-treated patients. At lower concentrations (1 nM and 10 nM), Cabo treatment failed to inhibit HGF (c-Met ligand)-induced c-Met phosphorylation. Instead, it further enhanced receptor phosphorylation and downstream signaling events for tumor growth. Additionally, Cabo treatment induced AXL-c-Met association and disrupted the physiological degradation of c-Met. However, inhibition or knockout of AXL could significantly overcome therapeutic resistance to c-Met inhibitor(s). It triggered apoptotic cell death through increased oxidative stress and inhibition of the redox-sensitive transcription factor, Nrf2 and its effector molecule, heme oxygenase-1 (HO-1). We also generated Cabo-resistant RCC cells and observed a marked upregulation of both c-Met and AXL in these cells. Epigenomic profiling revealed significant differences between Cabo-resistant and Cabo-sensitive RCC cells. Importantly, inhibition of AXL either using a potent inhibitor, TP-0903, or through genetic silencing resensitized the resistant cells to Cabo-induced cell death. Together, our findings highlight AXL as a key driver of therapeutic resistance to c-Met inhibitors. A combination therapy targeting both c-Met and AXL in renal cancer could be a promising strategy to overcome the acquired resistance to c-Met inhibitors through increased oxidative stress.