The RASAL2 variant promotes aberrant RAS signaling and resistance to anti-EGFR therapy in colorectal cancer.

Anti-EGFR monoclonal antibodies are essential for metastatic colorectal cancer (CRC) treatment, however, resistance remains problematic in KRAS/NRAS/BRAF wild-type patients. RAS protein activator-like 2 (RASAL2) regulates RAS signaling by catalyzing the conversion of RAS. This study investigates the pathogenicity of the germline RASAL2 c.2423 A > G variant, identified in a high-risk family, and its potential role in CRC progression and therapy resistance. Population analysis reveals its rarity in East Asians (0.01%) but an increased prevalence in Taiwanese CRC patients (1.63%). Functional studies demonstrate that RASAL2 c.2423 A > G enhances RAS signaling, causing sustained ERK phosphorylation and increased CRC cell proliferation. Additionally, RASAL2-mutant cells require higher doses of cetuximab for ERK suppression and growth inhibition, indicating resistance to anti-EGFR therapy via abnormal RAS activation. According to the American College of Medical Genetics and Genomics criteria, the variant is likely pathogenic. Our study highlights RASAL2 c.2423 A > G as a potential biomarker for CRC risk and therapy response.