Targeting RAC1 in glioblastoma: prognostic value, immune landscape, and small molecule therapeutic potential

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• RAC1, a Rho GTPase, is implicated in cell motility and irregularly expressed in solid tumors.
• Its specific roles in tumor cell states and impact on the immune microenvironment are not well understood.

Purpose of the Study:

• To evaluate RAC1 expression and its prognostic value across various cancers.
• To investigate RAC1's influence on the Glioblastoma (GBM) tumor microenvironment and potential therapeutic strategies.

Main Methods:

• Utilized TCGA, HPA, CPTAC, and GEO databases for expression and prognostic analysis.
• Performed cell line and tissue validation (qPCR, Western blotting), functional assays (proliferation, migration, invasion), and single-cell RNA sequencing.
• Analyzed immune infiltration, immunotherapy response, and drug sensitivity, including molecular docking for drug evaluation.

Main Results:

• RAC1 is upregulated in most cancers, with high prognostic accuracy in GBM (HR=2.61).
• RAC1 activation state, not total protein, affects GBM cell behavior; NSC23766 inhibited proliferation, migration, and invasion.
• Single-cell analysis identified RAC1 enrichment in NPC-like GBM cells, linked to IFN-gamma pathway activation and MHC-I upregulation, correlating with ICI resistance.
• Palbociclib demonstrated dose- and time-dependent inhibition of GBM cell viability.

Conclusions:

• RAC1 is a significant prognostic biomarker and therapeutic stratification indicator in GBM.
• RAC1-high GBM subpopulations are IFN-responsive and may benefit from CDK4/6 inhibitors over ICI monotherapy.