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. 2025 Jul 22.
doi: 10.1097/HEP.0000000000001474. Online ahead of print.

NEK7-induced phosphorylation of EGFR on serine 1070 drives the acquired lenvatinib resistance in hepatocellular carcinoma

Qibo Huang  1   2   3 , Weijian Wang  1   2   3 , Qianyun Ge  4 , Dafeng Xu  1   2   3   5 , Renshun Dong  1   2   3 , Ruizhi Chang  1   2   3 , Xing Wu  1   2   3 , Jie Mo  6 , Chen Su  1   2   3 , Deng Ning  7 , Qiumeng Liu  1   2   3   8   9 , Huifang Liang  1   2   3   8   9 , Guihua Wang  10 , Jin Chen  1   2   3   8   9 , Xifeng Fu  11   12 , Xiaoping Chen  1   2   3   8   9 , Junnan Liang  1   2   3   8   9 , Bixiang Zhang  1   2   3   8   9
Affiliations

NEK7-induced phosphorylation of EGFR on serine 1070 drives the acquired lenvatinib resistance in hepatocellular carcinoma

Qibo Huang et al. Hepatology. .

Abstract

Background and aims: Lenvatinib is recognized as a first-line therapy for inoperable hepatocellular carcinoma (HCC) patients. Growing evidence indicates that lenvatinib resistance can be acquired in HCC cells via kinase rewiring.

Approach and results: We established acquired lenvatinib-resistant organoids and HCC cell lines. NIMA-related coiled-coil kinase 7 (NEK7) was identified as an HCC lenvatinib acquired resistance gene by kinase CRISPR-Cas9 genetic screen. Functional analyses demonstrate that NEK7 enhanced lenvatinib resistance in HCC, and NEK7 knockdown or knockout displays the antitumor effects in acquired lenvatinib HCC cells and organoids. Mechanistically, NEK7 binds to the endothelial growth factor receptor (EGFR), leading to the phosphorylation of EGFR specifically at the serine 1070 residue, which contributes to the activation of MAPK (mitogen-activated protein kinase) and PI3K/AKT (phosphoinositide 3-kinase/Akt) signaling pathways. Consistently, designed inhibitory peptides targeting the domain from amino acids 979 to 1099 were proven to inhibit phosphorylation of EGFR S1070 site and therapeutically inhibit antitumor activity of acquired lenvatinib resistance HCC.

Conclusions: Our results unveil insights into the acquired lenvatinib resistance mechanism that NEK7 phosphorylates EGFR at S1070 to promote acquired lenvatinib resistance in HCC.

Keywords: NEK7; acquired lenvatinib resistance; endothelial growth factor receptor; hepatocellular carcinoma; kinase rewiring; patient-derived organoids.

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