Genomic Landscape, Targeted Therapies, and Mechanisms of Resistance in Molecularly Selected Metastatic Colorectal Cancer Patients

Metastatic colorectal cancer (mCRC) remains one of the leading causes of cancer-related mortality worldwide despite substantial therapeutic improvements over the past two decades. Advances in the understanding of colorectal tumor biology and oncogenic signaling have enabled the development of biomarker-guided therapies targeting alterations in EGFR, BRAFV600E, KRAS mutations and HER2 amplifications, improving outcomes in selected patient populations. Nevertheless, the emergence of both intrinsic and acquired resistance mechanisms continues to limit the durability of these responses. Resistance to targeted therapies in mCRC arises through multiple, often convergent mechanisms, including activation of compensatory signaling pathways, pre-existing genomic heterogeneity, and therapy-driven clonal selection. The integration of molecular profiling into clinical decision-making is essential to guide treatment selection and optimize therapeutic sequencing, ultimately enabling progress in precision oncology. Advances in genomic technologies, particularly circulating tumor DNA (ctDNA) analysis, have allowed longitudinal monitoring of tumor evolution, providing important insights into the mechanisms underlying resistance to targeted therapies. The aim of this review is to summarize the genomic landscape of mCRC and discuss current targeted therapeutic strategies in molecularly defined subgroups, with a particular focus on the mechanisms driving primary and acquired resistance.