EGFR activation limits the response of liver cancer to lenvatinib.

Autor: Jin H; 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., Shi Y; Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Lv Y; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Yuan S; The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Ramirez CFA; Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Lieftink C; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Wang L; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Wang S; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang C; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Dias MH; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Jochems F; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Yang Y; The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China., Bosma A; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Hijmans EM; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., de Groot MHP; Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Vegna S; Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Cui D; Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zhou Y; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Ling J; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Wang H; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Guo Y; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Zheng X; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China., Isima N; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Wu H; Department of Cell and Chemical Biology, Leiden University Medical Centre, Leiden, The Netherlands., Sun C; Division of Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands.; Immune Regulation in Cancer Group, German Cancer Research Center, Heidelberg, Germany., Beijersbergen RL; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Akkari L; Division of Tumour Biology and Immunology, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands., Zhou W; The Third Department of Hepatic Surgery, Eastern Hepatobiliary Surgery Hospital, Shanghai, China. ehphwp@126.com., Zhai B; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhaiboshi@sina.com.; Department of Interventional Oncology, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. zhaiboshi@sina.com., Qin W; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China. wxqin@sjtu.edu.cn., Bernards R; Division of Molecular Carcinogenesis, Oncode Institute, The Netherlands Cancer Institute, Amsterdam, The Netherlands. r.bernards@nki.nl.
Jazyk: angličtina
Zdroj: Nature [Nature] 2021 Jul; Vol. 595 (7869), pp. 730-734. Date of Electronic Publication: 2021 Jul 21.
DOI: 10.1038/s41586-021-03741-7
Abstrakt: Hepatocellular carcinoma (HCC)-the most common form of liver cancer-is an aggressive malignancy with few effective treatment options 1 . 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 2 . 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.
(© 2021. The Author(s), under exclusive licence to Springer Nature Limited.)
Databáze: MEDLINE
Externí odkaz: