Hepatocellular carcinoma (HCC)—the most common form of liver cancer—is an aggressive malignancy with few effective treatment options¹. Lenvatinib is a small-molecule inhibitor of multiple receptor tyrosine kinases that is used for the treatment of patients with advanced HCC, but this drug has only limited clinical benefit². Here, using a kinome-centred CRISPR–Cas9 genetic screen, we show that inhibition of epidermal growth factor receptor (EGFR) is synthetic lethal with lenvatinib in liver cancer. The combination of the EGFR inhibitor gefitinib and lenvatinib displays potent anti-proliferative effects in vitro in liver cancer cell lines that express EGFR and in vivo in xenografted liver cancer cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition of fibroblast growth factor receptor (FGFR) by lenvatinib treatment leads to feedback activation of the EGFR–PAK2–ERK5 signalling axis, which is blocked by EGFR inhibition. Treatment of 12 patients with advanced HCC who were unresponsive to lenvatinib treatment with the combination of lenvatinib plus gefitinib (trial identifier NCT04642547) resulted in meaningful clinical responses. The combination therapy identified here may represent a promising strategy for the approximately 50% of patients with advanced HCC who have high levels of EGFR.

肝细胞癌 (HCC) - 最常见的肝癌形式 - 是一种侵袭性恶性肿瘤，几乎没有有效的治疗选择¹。Lenvatinib 是一种多受体酪氨酸激酶的小分子抑制剂，用于治疗晚期 HCC 患者，但该药物的临床获益有限². 在这里，我们使用以激酶组为中心的 CRISPR-Cas9 基因筛选，表明表皮生长因子受体 (EGFR) 的抑制是乐伐替尼对肝癌的合成致死作用。EGFR 抑制剂吉非替尼和乐伐替尼的组合在体外对表达 EGFR 的肝癌细胞系以及在体内异种移植肝癌细胞系、免疫活性小鼠模型和小鼠中患者来源的 HCC 肿瘤中显示出有效的抗增殖作用。从机制上讲，乐伐替尼治疗对成纤维细胞生长因子受体 (FGFR) 的抑制会导致 EGFR–PAK2–ERK5 信号轴的反馈激活，而这会被 EGFR 抑制所阻断。乐伐替尼联合吉非替尼（试验编号 NCT04642547）对乐伐替尼治疗无反应的 12 名晚期 HCC 患者产生了有意义的临床反应。对于大约 50% 具有高水平 EGFR 的晚期 HCC 患者，此处确定的联合疗法可能代表一种有前途的策略。