Molecular Targeting of EGFR, BRAF, and HER2 Signaling in Colorectal Cancer: Contemporary Advances with Panitumumab, Encorafenib, and Tucatinib.

Metastatic colorectal cancer (mCRC) remains a major cause of cancer-related mortality worldwide. Advances in molecular profiling have transformed the therapeutic landscape, enabling biomarker-driven treatment strategies based on alterations in RAS, BRAF V600E, HER2 amplification, and mismatch repair status. Among these, dysregulation of the epidermal growth factor receptor (EGFR), BRAF, and HER2 signaling pathways represents a central driver of tumor progression and therapeutic resistance. Targeted agents directed against these pathways-including the anti-EGFR monoclonal antibody panitumumab, the selective BRAF inhibitor encorafenib, and the HER2-selective tyrosine kinase inhibitor tucatinib-have substantially expanded treatment options for molecularly defined subgroups of patients with mCRC. Anti-EGFR therapy remains a cornerstone of treatment for patients with RAS/BRAF wild-type, left-sided tumors. Panitumumab combined with chemotherapy has demonstrated significant improvements in response rates and overall survival compared with anti-angiogenic-based regimens in randomized clinical trials. For tumors harboring BRAF V600E mutations, which are associated with poor prognosis, combination strategies incorporating encorafenib with EGFR blockade have shown clinically meaningful survival benefits and represent an important therapeutic advance. In HER2-amplified colorectal cancer, HER2-targeted therapies have emerged as an effective treatment strategy. Trastuzumab-based combinations and HER2-selective tyrosine kinase inhibitors such as tucatinib have demonstrated durable responses and favorable safety profiles in heavily pretreated patients. This review summarizes current evidence from pivotal phase II and III clinical trials, translational studies, and real-world data evaluating EGFR-, BRAF-, and HER2-directed therapies in colorectal cancer. Particular emphasis is placed on biomarker-guided patient selection, mechanisms of resistance, and emerging combination strategies that continue to refine precision oncology approaches in mCRC.