In conclusion, our study shows that the resistance of HCC cells to multi-targeted tyrosine kinase inhibitors such as sorafenib and sunitinib is mediated by lysosomal sequestration (which is particularly evident in HCC cells with epithelial features), a mechanism that can be modulated by MDRP blockers such as verapamil. Here, BET1 is linked to hepatocellular carcinoma.