PREX2 is a guanine nucleotide exchange factor (GEF) that activates RAC1 by promoting GDP-to-GTP exchange, functioning downstream of both G protein-coupled receptors and phosphoinositide 3-kinase (PI3K) 1. Its activity is synergistically enhanced by phosphatidylinositol 3,4,5-trisphosphate and G protein βγ subunits, with mechanistic involvement in the PI3K/AKT signaling pathway 12. PREX2 interacts with PTEN, regulating its protein stability and activity; truncating mutations abolish PTEN binding while activating RAC1 GEF activity 1. Clinically, PREX2 exhibits oncogenic roles across multiple cancer types. In pancreatic ductal adenocarcinoma, PREX2 gene disruption occurs as a driver of carcinogenesis 3. In colorectal cancer, PREX2 overexpression confers radiation resistance by suppressing immunogenic cell death through the cGAS/STING/IFN pathway and promoting DNA repair 4. In NRAS-mutant melanoma, truncating PREX2 mutations promote tumorigenesis by deregulating cell cycle and cytoskeleton genes through epigenetic mechanisms, including CDKN1C downregulation 12. In non-small cell lung cancer, PREX2 promotes tumor growth through interaction with AHCYL1, which enhances its GEF activity 5. In BRAF-mutant melanoma, the PREX2/RAC1/PI3Kβ axis drives therapeutic resistance, and dual targeting of MAPK and this pathway shows superior efficacy 6. PREX2 mutations in hepatocellular carcinoma, particularly S1113R, increase protein stability and promote aggressive behavior 7.