It has been reported that cancer-associated fibroblast-derived secreted phosphoprotein 1 enhances TKI resistance in HCC through bypassing the activation of carcinogenic signaling and promoting the EMT, activating MAPK and PI3K/AKT mammalian target of rapamycin (mTOR).32 Leung et al. demonstrated CDK6 as a druggable target in lenvatinib-resistant HCC. This evidence concerns the gene AKT1 and hepatocellular carcinoma.