TARGETED THERAPIES IN EMERGING MOLECULAR ALTERATIONS (KRAS G12C, BRAF, AND HER2) IN COLON CANCER: BIOLOGICAL BASES, CLINICAL EVIDENCE, AND IMPACT ON PRECISION MEDICINE

Abstract

Colon cancer exhibits marked molecular heterogeneity, and alterations involving KRAS G12C, BRAF V600E, and HER2 have become central to therapeutic stratification and the consolidation of precision oncology. This study aimed to analyze the biological foundations of these emerging molecular alterations, review current clinical evidence regarding their corresponding targeted therapies, and evaluate their impact on contemporary oncologic practice. A qualitative bibliographic review was conducted using major international databases, including studies published between 2021 and 2026. The findings indicate that KRAS G12C, once considered “undruggable,” has become a viable therapeutic target with the development of selective inhibitors, particularly when combined with anti-EGFR antibodies to mitigate adaptive signaling reactivation. In BRAF V600E-mutant tumors, combination strategies involving BRAF inhibitors, MEK inhibitors, and EGFR blockade have demonstrated significant survival benefits, redefining the therapeutic standard for this poor-prognosis subgroup. HER2 amplification or overexpression characterizes a distinct subset of RAS wild-type tumors, often resistant to isolated anti-EGFR therapy but responsive to dual anti-HER2 blockade. Despite these advances, primary and acquired resistance—driven by tumor heterogeneity, clonal evolution, and metabolic plasticity—remains a major clinical challenge. In conclusion, the integration of molecular biology, longitudinal genomic monitoring, and rational combination strategies is essential to optimize outcomes and further consolidate personalized medicine in colon cancer.