2. Academic Validation
  3. GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma

GOLM1 dictates acquired Lenvatinib resistance by a GOLM1-CSN5 positive feedback loop upon EGFR signaling activation in hepatocellular carcinoma

  • Oncogene. 2024 Oct;43(42):3108-3120. doi: 10.1038/s41388-024-03153-7.
Peiyi Xie # 1,  Mengyuan Wu # 2,  Hui Wang # 3,  Bo Zhang # 1,  Zihao Zhang # 4,  Jiuliang Yan 5,  Mincheng Yu 1,  Qiang Yu 1,  Yufei Zhao 1,  Da Huang 6,  Min Xu 1,  Wenxin Xu 1,  Hui Li 7 8,  Yongfeng Xu 9,  Yongsheng Xiao 10,  Lei Guo 11
Affiliations

Affiliations

  • 1 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China.
  • 2 Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
  • 3 Department of Molecular Biology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200032, PR China.
  • 4 Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, 200032, PR China.
  • 5 Department of Pancreatic Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200080, PR China.
  • 6 Department of Thyroid Surgery, Second Affiliated Hospital of Nanchang University, Nanchang, 330000, PR China.
  • 7 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China. li.hui1@zs-hospital.sh.cn.
  • 8 Shanghai Medical College and Zhongshan Hospital Immunotherapy Technology Translational Research Center, Shanghai, 200031, PR China. li.hui1@zs-hospital.sh.cn.
  • 9 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China. xu.yongfeng@zs-hospital.sh.cn.
  • 10 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China. xiao.yongsheng@zs-hospital.sh.cn.
  • 11 Department of Liver Surgery and Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai, 200032, PR China. guo.lei@zs-hospital.sh.cn.
  • # Contributed equally.
PMID: 39251847 DOI: 10.1038/s41388-024-03153-7
Abstract

Lenvatinib is a multiple Receptor Tyrosine Kinases inhibitor (TKI) authorized for first-line treatment of hepatocellular carcinoma (HCC). However, Lenvatinib resistance is common in HCC clinical treatment, highlighting the urgent need to understand mechanisms of resistance. Here, we identified Golgi membrane protein 1 (GOLM1), a type II transmembrane protein originally located in the Golgi apparatus, as a novel regulator of Lenvatinib resistance. We found GOLM1 was overexpressed in Lenvatinib resistant human HCC cell lines, blood and HCC samples. Additionally, GOLM1 overexpression contributes to Lenvatinib resistance and HCC progression in vitro and in vivo. Mechanistically, GOLM1 upregulates CSN5 expression through EGFR-STAT3 pathway. Reversely, CSN5 deubiquitinates and stabilizes GOLM1 protein by inhibiting ubiquitin-proteasome pathway of GOLM1. Furthermore, clinical specimens of HCC showed a positive correlation between the activation of the GOLM1-EGFR-STAT3-CSN5 axis. Finally, GOLM1 knockdown was found to act in synergy with Lenvatinib in subcutaneous and orthotopic mouse model. Overall, these findings identify a mechanism of resistance to Lenvatinib treatment for HCC, highlight an effective predictive biomarker of Lenvatinib response in HCC and show that targeting GOLM1 may improve the clinical benefit of Lenvatinib.

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