This review article aims to address the challenges associated with targeted therapy for the treatment of metastatic colorectal cancer (mCRC). We will first provide an overview of approved targeted therapies for treating mCRC, which include antiangiogenic therapy, as well as inhibitors of EGFR, BRAFV600E, HER2 inhibitors, and immune checkpoints. Second, we discuss the different mechanisms of primary resistance, including tumor heterogeneity, both as inter-patient and intra-patient heterogeneity, and mechanisms of secondary resistance which include: driver oncogene alterations, downstream or parallel bypass signaling, presence of co-dominant driver oncogenes, tumor lineage plasticity, and epithelial to mesenchymal transition. Resistance mechanisms towards the different drug classes targeting mCRC are discussed in detail. Strategies to overcome resistance primarily involve combination of therapies, although this approach is typically linked to increased drug toxicity, manifesting as on and off-target effects. Moreover, the cost and accessibility of targeted therapies pose significant challenges for diverse populations. Addressing these challenges necessitates further research efforts aimed at optimizing the use of targeted therapy in mCRC. Integration of genomic biomarkers, such as sequencing and liquid biopsy, into routine clinical practice holds promise in enhancing treatment outcomes. In conclusion, this comprehensive review underscores the complex challenges encountered in targeted therapy for mCRC.
Keywords: acquired resistance; biomarkers; combination therapy in metastatic colorectal cancer; mCRC treatment; mode of resistance to EGFR inhibitors; primary resistance; resistance to Her2 inhibition; resistance to antiangiogenic therapy; targeted therapy; tumor heterogeneity.