Open Access

ARTICLE

Degradation of FAK-targeting by proteolytic targeting chimera technology to inhibit the metastasis of hepatocellular carcinoma

XINFENG ZHANG^1,2,#, SHUANG LI^2,#, MEIRU SONG^1,2, YUE CHEN³, LIANGZHENG CHANG³, ZHERUI LIU⁴, HONGYUAN DAI³, YUTAO WANG⁴, GANGQI YANG³, YUN JIANG^5,6,*, YINYING LU^1,2,*

1 The PLA 307 Clinical College of Anhui Medical University, The Fifth Clinical Medical College of Anhui Medical University, Hefei, 230032, China
2 Liver Tumor Diagnosis and Research Center, 5th Medical Center of the PLA General Hospital, Beijing, 100039, China
3 Department of Infection Diseases, Guizhou Medical University, Guiyang, 550025, China
4 302 Clinical Medical School, Peking University, Beijing, China
5 Cell and Gene Therapy Innovation Center, Beijing Lotuslake Biomedical, Science and Technology Park, Beijing, 102206, China
6 State Key Laboratory of Chemical Oncogenomics and the Institute of Biopharmaceutical and Health Engineering (iBHE), Shenzhen International Graduate School, Tsinghua University, Shenzhen, 518055, China

* Corresponding Authors: YUN JIANG. Email: ; YINYING LU. Email:
# These authors share first authorship

(This article belongs to the Special Issue: Cancer Metastasis)

Oncology Research 2024, 32(4), 679-690. https://doi.org/10.32604/or.2024.046231

Received 24 September 2023; Accepted 07 December 2023; Issue published 20 March 2024

Abstract

Liver cancer is a prevalent malignant cancer, ranking third in terms of mortality rate. Metastasis and recurrence primarily contribute to the high mortality rate of liver cancer. Hepatocellular carcinoma (HCC) has low expression of focal adhesion kinase (FAK), which increases the risk of metastasis and recurrence. Nevertheless, the efficacy of FAK phosphorylation inhibitors is currently limited. Thus, investigating the mechanisms by which FAK affects HCC metastasis to develop targeted therapies for FAK may present a novel strategy to inhibit HCC metastasis. This study examined the correlation between FAK expression and the prognosis of HCC. Additionally, we explored the impact of FAK degradation on HCC metastasis through wound healing experiments, transwell invasion experiments, and a xenograft tumor model. The expression of proteins related to epithelial-mesenchymal transition (EMT) was measured to elucidate the underlying mechanisms. The results showed that FAK PROTAC can degrade FAK, inhibit the migration and invasion of HCC cells in vitro, and notably decrease the lung metastasis of HCC in vivo. Increased expression of E-cadherin and decreased expression of vimentin indicated that EMT was inhibited. Consequently, degradation of FAK through FAK PROTAC effectively suppressed liver cancer metastasis, holding significant clinical implications for treating liver cancer and developing innovative anti-neoplastic drugs.

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Keywords

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