Splicing Shift of RAC1 Accelerates Tumorigenesis and Defines a Potent Therapeutic Target in Lung Cancer

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Dysregulated RNA splicing is a key feature in cancer development.
• The functional roles of RAC1 isoforms (RAC1A and RAC1B) in cancer are not well understood.
• RAC1B is upregulated in lung adenocarcinoma (LUAD), particularly with EGFR mutations.

Purpose of the Study:

• To investigate the in vivo functional differences between RAC1A and RAC1B isoforms in EGFR-mutant LUAD.
• To elucidate the molecular mechanisms by which RAC1B contributes to LUAD tumorigenesis.
• To evaluate RAC1B as a therapeutic target in LUAD.

Main Methods:

• Isoform-specific overexpression and depletion assays in cellular and murine models of EGFR-mutant LUAD.
• Analysis of RAC1B-GDS1 interaction and its effect on EGFR stability.
• Investigation of RBM10 as a regulator of RAC1B.
• Validation in patient-derived organoid and xenograft models.

Main Results:

• RAC1B, not RAC1A, significantly promotes LUAD cell proliferation and tumor growth.
• RAC1B stabilizes EGFR by preventing lysosomal degradation, mediated by GDS1.
• Splicing factor RBM10 acts as a negative regulator of RAC1B.
• Targeting RAC1B suppressed tumor growth and improved EGFR inhibitor efficacy in preclinical models.

Conclusions:

• RAC1B plays a critical role in EGFR-mutant LUAD progression through EGFR stabilization.
• RAC1B is a potential therapeutic target for LUAD, enhancing current EGFR-targeted therapies.
• Understanding RAC1 isoform function provides insights into LUAD tumorigenesis and treatment strategies.