EGFR activation limits the response of liver cancer to lenvatinib

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...

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Vydáno v:	Nature (London) Ročník 595; číslo 7869; s. 730 - 734
Hlavní autoři:	Jin, Haojie, Shi, Yaoping, Lv, Yuanyuan, Yuan, Shengxian, Ramirez, Christel F. A., Lieftink, Cor, Wang, Liqin, Wang, Siying, Wang, Cun, Dias, Matheus Henrique, Jochems, Fleur, Yang, Yuan, Bosma, Astrid, Hijmans, E. Marielle, de Groot, Marnix H. P., Vegna, Serena, Cui, Dan, Zhou, Yangyang, Ling, Jing, Wang, Hui, Guo, Yuchen, Zheng, Xingling, Isima, Nikita, Wu, Haiqiu, Sun, Chong, Beijersbergen, Roderick L., Akkari, Leila, Zhou, Weiping, Zhai, Bo, Qin, Wenxin, Bernards, René
Médium:	Journal Article
Jazyk:	angličtina
Vydáno:	London Nature Publishing Group UK 29.07.2021 Nature Publishing Group
Témata:	38 38/47 38/89 38/90 38/91 631/67/1059 631/67/68 96/106 Animal models Animals Antineoplastic Agents - pharmacology Cancer Cancer therapies Carcinoma, Hepatocellular - drug therapy Carcinoma, Hepatocellular - metabolism Causes of Cell culture Cell Line, Tumor CRISPR Development and progression Drug resistance Drug Resistance, Neoplasm Drug therapy Epidermal growth factor Epidermal growth factor receptors ErbB Receptors - antagonists & inhibitors ErbB Receptors - metabolism Feedback Female Fibroblast growth factor receptors Gefitinib Gefitinib - pharmacology Genetic screening Growth factors Hepatocellular carcinoma Hepatocytes Hepatoma Humanities and Social Sciences Humans Immunocompetence Inhibitor drugs Kinases Liver cancer Liver Neoplasms - drug therapy Liver Neoplasms - metabolism Male Malignancy Mice Mice, Inbred BALB C Mice, Nude multidisciplinary Patients Phenylurea Compounds - pharmacology Phosphorylation Physiological aspects Quinolines - pharmacology Receptors Receptors, Fibroblast Growth Factor Science Science (multidisciplinary) Signal Transduction Targeted cancer therapy Tumor cell lines Tumors Tyrosine Xenograft Model Antitumor Assays Xenografts China
ISSN:	0028-0836, 1476-4687, 1476-4687
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Shrnutí:	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. EGFR inhibition and lenvatinib treatment of liver cancer cells in vitro and in in vivo mouse models has potent anti-proliferative effects, and lenvatinib plus gefitinib treatment of 12 patients with advanced liver cancer resulted in meaningful clinical responses.
Bibliografie:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 14 content type line 23
ISSN:	0028-0836 1476-4687 1476-4687
DOI:	10.1038/s41586-021-03741-7