Our group previously identified EGFR as a synthetic lethal target of lenvatinib in HCC by using CRISPR-Cas9 genetic screen.53 One of the mechanisms of intrinsic resistance to lenvatinib treatment in HCC is the inhibition of fibroblast growth factor receptor (FGFR) leading to a feedback activation of the EGFR-PAK2-ERK1/2 and EGFR-PAK2-ERK5 signaling pathways, which allows malignant cells to maintain survival and sustain proliferation. The gene discussed is PAK2; the disease is hepatocellular carcinoma.