Author
Listed:
- Haojie Jin
(Shanghai Jiao Tong University School of Medicine
Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute)
- 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
Immune Regulation in Cancer Group, German Cancer Research Center)
- 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
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)
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.
Suggested Citation
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, 2021.
"EGFR activation limits the response of liver cancer to lenvatinib,"
Nature, Nature, vol. 595(7869), pages 730-734, July.
Handle:
RePEc:nat:nature:v:595:y:2021:i:7869:d:10.1038_s41586-021-03741-7
DOI: 10.1038/s41586-021-03741-7
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Cited by:
- Stephan Spahn & Fabian Kleinhenz & Ekaterina Shevchenko & Aaron Stahl & Yvonne Rasen & Christine Geisler & Kristina Ruhm & Marion Klaumuenzer & Thales Kronenberger & Stefan A. Laufer & Holly Sundberg-, 2024.
"The molecular interaction pattern of lenvatinib enables inhibition of wild-type or kinase-mutated FGFR2-driven cholangiocarcinoma,"
Nature Communications, Nature, vol. 15(1), pages 1-13, December.
- Yunxing Shi & Zongfeng Wu & Shaoru Liu & Dinglan Zuo & Yi Niu & Yuxiong Qiu & Liang Qiao & Wei He & Jiliang Qiu & Yunfei Yuan & Guocan Wang & Binkui Li, 2024.
"Targeting PRMT3 impairs methylation and oligomerization of HSP60 to boost anti-tumor immunity by activating cGAS/STING signaling,"
Nature Communications, Nature, vol. 15(1), pages 1-21, December.
- Carmen Oi Ning Leung & Yang Yang & Rainbow Wing Hei Leung & Karl Kam Hei So & Hai Jun Guo & Martina Mang Leng Lei & Gregory Kenneth Muliawan & Yuan Gao & Qian Qian Yu & Jing Ping Yun & Stephanie Ma & , 2023.
"Broad-spectrum kinome profiling identifies CDK6 upregulation as a driver of lenvatinib resistance in hepatocellular carcinoma,"
Nature Communications, Nature, vol. 14(1), pages 1-20, December.
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