Targeting AXL can effectively inhibit c-Met-induced therapeutic resistance in renal cancer
The mechanism(s) for therapeutic resistance against c-Met/receptor tyrosine kinase (RTK) inhibitor(s) in renal cancer is totally unexplored. In renal cell carcinoma (RCC) cells, both AXL and c-Met are highly overexpressed and they form a complex. Interestingly, the prolonged treatment with c-Met/RTK inhibitor, Cabozantinib (Cabo), which is being used for the treatment of RCC patients, markedly increased the level of total c-Met 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. Also, the lower concentrations of Cabo treatment could not inhibit HGF (c-Met ligand)-induced c-Met phosphorylation; rather they further increased the phosphorylation of the receptor and promoted downstream signaling events for tumor growth. In addition, our findings indicate that Cabo treatment induces AXL-c-Met association, and it interferes with the physiological degradation processes of c-Met within renal cancer cells. However, either the inhibition or the knockout of AXL could significantly overcome the therapeutic resistance against c-Met inhibitor(s); and it markedly induced apoptotic cell death through increased oxidative stress and inhibition of the transcription factor, Nrf2. We generated Cabo-resistant RCC cells, and we observed that the expression of both c-Met and AXL are markedly overexpressed in these cells; and the inhibition of AXL (through TP-0903) can   resensitize the cancer cells to Cabo-mediated cell death. Moreover, we found significant differences in the epigenomic profile of the Cabo-resistant RCC cells compared with Cabo-sensitive cancer cells. Our in-depth studies suggest that AXL plays a major role in mediating therapeutic resistance against c-Met inhibitor(s). A combination therapy using c-Met inhibitor(s) in the presence of an AXL inhibitor can play a pivotal role to overcome acquired resistance against RTK inhibitors in renal cancer. Overall design: RNA-seq and ChIP-seq of the histone modifcation H3K27ac were performed in cabozantinib-sensitive and cabozantinib-resistant renal cell carcinoma cell lines