小柯机器人

EGFR激活阻碍仑伐替尼在肝癌中的治疗效果，这一成果由上海交通大学医学院附属仁济医院上海市肿瘤研究所覃文新、翟博、上海东方肝胆外科医院周伟平以及荷兰癌症研究所Rene-Bernards研究组合作取得。相关论文于2021年7月21日发表在《自然》杂志上。

研究人员使用靶向激酶组的CRISPR-Cas9遗传筛选，发现在肝癌中抑制表皮生长因子受体 (EGFR) 联合使用仑伐替尼会造成合成致死的。EGFR抑制剂吉非替尼联合仑伐替尼可对体外表达EGFR的肝癌细胞系和体内异种移植肝癌细胞系、免疫活性小鼠模型和患者来源的肝细胞癌 (HCC)肿瘤小鼠产生有效的抗增殖作用。

从机制上讲，仑伐替尼治疗对成纤维细胞生长因子受体 (FGFR)的抑制反馈激活了EGFR-PAK2-ERK5 信号通路，该通路被EGFR抑制剂所阻断。对乐伐替尼治疗无反应的12名晚期HCC患者使用仑伐替尼联合吉非替尼（试验编号 NCT04642547）的治疗产生了有意义的临床数据。对于大约50%高表达EGFR的晚期HCC患者来说，以上联合疗法可能是一种有前景的治疗策略。

据了解，HCC是最常见的肝癌形式，也是一种具有侵袭性的恶性肿瘤，几乎没有有效的治疗方法。仑伐替尼是一种靶向多受体酪氨酸激酶的小分子抑制剂，用于治疗晚期 HCC 患者，但这种药物的临床效果有限。

附：英文原文

Title: EGFR activation limits the response of liver cancer to lenvatinib

Author: Haojie Jin, Yaoping Shi, Yuanyuan Lv, Shengxian Yuan, Christel F. A. Ramirez, Cor Lieftink, Liqin Wang, Siying Wang, Cun Wang, Matheus Henrique Dias, Fleur Jochems, Yuan Yang, Astrid Bosma, E. Marielle Hijmans, Marnix H. P. de Groot, Serena Vegna, Dan Cui, Yangyang Zhou, Jing Ling, Hui Wang, Yuchen Guo, Xingling Zheng, Nikita Isima, Haiqiu Wu, Chong Sun, Roderick L. Beijersbergen, Leila Akkari, Weiping Zhou, Bo Zhai, Wenxin Qin, Ren Bernards

Issue&Volume: 2021-07-21

Abstract: 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.

DOI: 10.1038/s41586-021-03741-7

Source: https://www.nature.com/articles/s41586-021-03741-7

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