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  3. A genome-wide screen identified ARHGAP35 as a regulator of regorafenib resistance in liver cancer

A genome-wide screen identified ARHGAP35 as a regulator of regorafenib resistance in liver cancer

  • Anticancer Drugs. 2025 Oct 16. doi: 10.1097/CAD.0000000000001775.
Kun Chen 1,  Miaomiao Zhang 1,  Yuexin Liu 1,  Zhengnan Dong 1,  Yaoji Liang 2 3,  Jinzhang Zeng 1,  Jie Liu 1
Affiliations

Affiliations

  • 1 Fujian Provincial Key Laboratory of Innovative Drug Target Research, School of Pharmaceutical Sciences.
  • 2 Department of Colorectal Tumor Surgery, The First Affiliated Hospital of Xiamen University, School of Medicine, Xiamen University.
  • 3 Biochee Biotech, Xiamen, China.
PMID: 41176659 DOI: 10.1097/CAD.0000000000001775
Abstract

Regorafenib, a multikinase inhibitor, is widely used to treat hepatocellular carcinoma. However, chemoresistance poses a significant challenge to its long-term efficacy. This study conducted a genome-wide CRISPR/Cas9 knockout screen in liver Cancer cell lines to identify key regulators of regorafenib resistance and elucidate the underlying molecular mechanisms. The screen identified ARHGAP35 as a critical negative regulator of regorafenib resistance. ARHGAP35 depletion conferred resistance in HepG2 and Huh7 cells, while regorafenib-resistant variants (HepG2-R and Huh7-R) exhibited decreased ARHGAP35 expression. Reintroducing ARHGAP35 restored drug sensitivity. Further analysis revealed that reduced ARHGAP35 expression facilitated epithelial-mesenchymal transition (EMT) by activating the RhoA signaling pathway. Notably, RhoA inhibition reversed EMT and restored regorafenib sensitivity. These findings highlight ARHGAP35 as a key modulator of regorafenib resistance through RhoA suppression, offering potential therapeutic targets to combat chemoresistance in liver Cancer.

Keywords

ARHGAP35; genome-wide screening; liver cancer; resisitance.

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