EGFR activation limits the response of liver cancer to lenvatinib

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. 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 () and René Bernards ()
Additional contact information
Haojie Jin: Shanghai Jiao Tong University School of Medicine
Yaoping Shi: Shanghai Jiao Tong University School of Medicine
Yuanyuan Lv: Shanghai Jiao Tong University School of Medicine
Shengxian Yuan: Eastern Hepatobiliary Surgery Hospital
Christel F. A. Ramirez: Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute
Cor Lieftink: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Liqin Wang: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Siying Wang: Shanghai Jiao Tong University School of Medicine
Cun Wang: Shanghai Jiao Tong University School of Medicine
Matheus Henrique Dias: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Fleur Jochems: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Yuan Yang: Eastern Hepatobiliary Surgery Hospital
Astrid Bosma: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
E. Marielle Hijmans: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Marnix H. P. Groot: Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute
Serena Vegna: Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute
Dan Cui: Shanghai Jiao Tong University School of Medicine
Yangyang Zhou: Shanghai Jiao Tong University School of Medicine
Jing Ling: Shanghai Jiao Tong University School of Medicine
Hui Wang: Shanghai Jiao Tong University School of Medicine
Yuchen Guo: Shanghai Jiao Tong University School of Medicine
Xingling Zheng: Shanghai Jiao Tong University School of Medicine
Nikita Isima: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Haiqiu Wu: Leiden University Medical Centre
Chong Sun: Division of Immunology, Oncode Institute, The Netherlands Cancer Institute
Roderick L. Beijersbergen: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute
Leila Akkari: Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute
Weiping Zhou: Eastern Hepatobiliary Surgery Hospital
Bo Zhai: Shanghai Jiao Tong University School of Medicine
Wenxin Qin: Shanghai Jiao Tong University School of Medicine
René Bernards: Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute

Nature, 2021, vol. 595, issue 7869, 730-734

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41586-021-03741-7

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