论文
论文标题：EGFR activation limits the response of liver cancer to lenvatinib
作者：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, René Bernards
期刊：Nature
发表时间：2021/07/21
数字识别码：10.1038/s41586-021-03741-7
摘要：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.
