Jin Haojie, Shi Yaoping, Lv Yuanyuan, Yuan Shengxian, Ramirez Christel F A, Lieftink Cor, Wang Liqin, Wang Siying, Wang Cun, Dias Matheus Henrique, Jochems Fleur, Yang Yuan, Bosma Astrid, Hijmans E Marielle, de Groot Marnix H P, Vegna Serena, Cui Dan, Zhou Yangyang, Ling Jing, Wang Hui, Guo Yuchen, Zheng Xingling, Isima Nikita, Wu Haiqiu, Sun Chong, Beijersbergen Roderick L, Akkari Leila, Zhou Weiping, Zhai Bo, Qin Wenxin, Bernards René
State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.
Nature. 2021 Jul;595(7869):730-734. doi: 10.1038/s41586-021-03741-7. Epub 2021 Jul 21.
Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options. 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 benefit. 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）是最常见的肝癌形式，是一种侵袭性恶性肿瘤，有效治疗选择很少。乐伐替尼是一种多受体酪氨酸激酶小分子抑制剂，用于治疗晚期HCC患者，但这种药物的临床益处有限。在这里，我们使用以激酶组为中心的CRISPR-Cas9基因筛选表明，在肝癌中，抑制表皮生长因子受体（EGFR）与乐伐替尼具有合成致死性。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对异种移植肝癌细胞系、免疫活性小鼠模型和小鼠体内患者来源的HCC肿瘤均显示出强大的抗增殖作用。从机制上讲，乐伐替尼治疗对成纤维细胞生长因子受体（FGFR）的抑制导致EGFR-PAK2-ERK5信号轴的反馈激活，而EGFR抑制可阻断该信号轴。用乐伐替尼加吉非替尼联合治疗12例对乐伐替尼治疗无反应的晚期HCC患者（试验标识符NCT04642547）产生了有意义的临床反应。这里确定的联合治疗可能是约50%EGFR水平高的晚期HCC患者的一种有前景的策略。
