Using an unbiased genome-scale CRISPR/Cas9-based screening in sorafenib resistant cells, we now independently identify KEAP1 as a sorafenib-sensitivity gene in both resistant and wild-type HCC cells and further extended these findings to the recently approved anti-HCC drugs, lenvatinib and regorafenib. The gene discussed is KEAP1; the disease is hepatocellular carcinoma.