Gain-of-Function RHOA Mutations Promote Focal Adhesion Kinase Activation and Dependency in Diffuse Gastric Cancer.

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Diffuse gastric cancer (DGC) is an aggressive malignancy with limited therapeutic options.
• Recurrent missense mutations in the GTPase RHOA are frequently observed in DGC, but their functional impact remains unclear.

Purpose of the Study:

• To elucidate the function of RHOA mutations in DGC.
• To investigate the downstream signaling pathways affected by RHOA mutations.
• To identify potential therapeutic targets for RHOA-mutated DGC.

Main Methods:

• Biochemical characterization of RHOA mutations.
• Development of a mouse model expressing RHOA^Y42C and Cdh1 inactivation.
• Analysis of downstream signaling pathways including FAK, YAP-TAZ, PI3K-AKT, and β-catenin.
• Assessment of therapeutic sensitivity in murine models and patient-derived cell lines.

Main Results:

• The RHOA^Y42C mutation confers gain-of-function oncogenic activity.
• RHOA^Y42C expression with Cdh1 loss induces metastatic DGC in mice.
• RHOA^Y42C impairs GTP hydrolysis, enhances ROCK interaction, and promotes cytoskeletal rearrangements.
• Activated FAK, YAP-TAZ, PI3K-AKT, and β-catenin pathways were observed.
• RHOA^Y42C-driven DGC models showed sensitivity to FAK inhibition and combined pathway blockade.

Conclusions:

• RHOA^Y42C is an activating oncogenic mutation driving DGC.
• RHOA-mediated FAK activation is a key mechanism in DGC pathogenesis.
• FAK inhibition represents a promising therapeutic strategy for DGC with RHOA mutations.