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Recurrent RhoGAP gene fusion CLDN18-ARHGAP26 promotes RHOA activation and focal adhesion kinase and YAP-TEAD

Feifei Zhang1,2, Varun Sahu3,4, Ke Peng2,5

  • 1Department of General Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China.

Gut
|April 15, 2024
PubMed
Abstract

Insights

The CLDN18-ARHGAP26 fusion protein drives diffuse gastric cancer (DGC) by activating RHOA, FAK, and YAP signaling. Targeting FAK and YAP/TEAD pathways offers a promising therapeutic strategy for DGC.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Genomic studies reveal recurrent alterations in RHO signaling in diffuse gastric cancer (DGC).
  • Specific alterations include fusions between CLDN18 and ARHGAP26, but their functional impact is unclear.
  • Understanding these fusions is crucial for identifying therapeutic targets in DGC.

Purpose of the Study:

  • To investigate the oncogenic function of the CLDN18-ARHGAP26 fusion protein in DGC pathogenesis.
  • To elucidate the molecular mechanisms by which this fusion impacts RHO signaling and downstream pathways.
  • To identify potential therapeutic strategies for DGC harboring this specific genomic alteration.

Main Methods:

  • Development of a transgenic mouse model with inducible CLDN18-ARHGAP26 expression.
  • Generation and analysis of gastric organoids derived from the transgenic model.
  • Biochemical and cell biological assays to assess RHOA pathway activation, FAK, and YAP signaling.

Main Results:

  • CLDN18-ARHGAP26 expression induced signet ring cell formation, a hallmark of DGC.
  • The fusion cooperatively transformed gastric cells with Trp53 loss, activating RHOA, FAK, and YAP pathways.
  • Combined inhibition of FAK and YAP/TEAD significantly suppressed tumor growth in organoid models.

Conclusions:

  • The CLDN18-ARHGAP26 fusion acts as a gain-of-function oncogene in DGC.
  • Activation of RHOA, FAK, and YAP signaling is a key mechanism driven by this fusion.
  • FAK and YAP-TEAD inhibitors represent promising therapeutic avenues for DGC patients with these alterations.
Keywords:
gastric cancermolecular oncology

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