Internal medicine

Receptor

Liver cancer

Lenvatinib

EGFR inhibitors

Hepatocellular carcinoma

Erlotinib

Epidermal growth factor receptor

Biology

Cancer

Oncology

Kinase

Sorafenib

Gefitinib

Kinome

Cell biology

Tyrosine kinase

Cancer research

Medicine

Pharmacology

Nature

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&nbsp;cell lines that express EGFR and in vivo in xenografted liver cancer&nbsp;cell lines, immunocompetent mouse models and patient-derived HCC tumours in mice. Mechanistically, inhibition&nbsp;of fibroblast growth factor receptor (FGFR)&nbsp; 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&nbsp;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.

EGFR activation limits the response of liver cancer to lenvatinib