Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance

Abstract

Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with RAS and BRAF wild-type cancer. Yet, primary and acquired resistance limit their benefit for many patients. A growing body of evidence reveals that resistance is not random but rather driven by a complex network of molecular alterations that sustain tumor growth independent of EGFR signaling. These include amplification of ERBB2 (HER2) and MET, activation of the PI3K and AKT pathways, EGFR extracellular domain mutations, and rare kinase fusions. The concept of negative hyperselection has emerged as a powerful strategy to refine patient selection by excluding tumors with these resistance drivers. Multiple clinical trials have consistently shown that patients who are hyperselected based on comprehensive molecular profiling achieve significantly higher response rates and improved survival compared to those selected by RAS and BRAF status alone. Liquid biopsy through circulating tumor DNA has further transformed this landscape, offering a noninvasive tool to capture tumor heterogeneity, monitor clonal evolution in real time, and guide rechallenge strategies after resistance emerges. Together, negative hyperselection, ctDNA-guided monitoring, and emerging therapeutics define a precision-oncology framework for identifying, tracking, and overcoming resistance to anti-EGFR therapy in mCRC, moving the field toward more effective and individualized care. Looking ahead, the development of innovative therapeutics such as bispecific antibodies, antibody drug conjugates, and RNA-based therapies promises to further expand in this challenging clinical scenario. These advances move precision oncology in colorectal cancer from concept to clinical reality, reshaping the standard of care through molecular insights.

Keywords: EGFR inhibition; circulating tumor DNA; metastatic colorectal cancer; negative hyperselection; precision oncology.

Figure 1

Mechanisms of primary resistance to anti-EGFR therapy in metastatic colorectal cancer. Several genetic alterations drive intrinsic resistance to EGFR-targeted monoclonal antibodies such as cetuximab and panitumumab. These include activating mutations in KRAS and BRAF, amplification or mutation of HER2 and MET, extracellular domain mutations in EGFR, and alterations in downstream signaling components such as PIK3CA, AKT1, MEK1, and PTEN. These molecular events activate parallel or downstream signaling cascades, including the RAS RAF MEK ERK and PI3K AKT mTOR pathways, which sustain tumor cell survival, proliferation, and disease progression independent of EGFR signaling blockade.

Figure 2

Mechanisms of Acquired Resistance to Anti-EGFR Therapy in Metastatic Colorectal Cancer. EGFR-targeted monoclonal antibodies (cetuximab or panitumumab) initially reduce tumor burden in RAS/BRAF wild-type colorectal cancer. However, under treatment pressure, resistant clones (e.g., with KRAS mutations) are positively selected or newly emerge through acquired mutations. These resistant subclones expand over subsequent treatment cycles, ultimately leading to disease progression despite continued anti-EGFR therapy.

Figure 3

Precision Oncology Framework for Anti-EGFR Therapy in Metastatic Colorectal Cancer. Liquid biopsy enables noninvasive, real-time molecular profiling across the treatment course. At baseline, panels assessing RAS/BRAF status and additional negative hyperselection markers (e.g., HER2, MET, MAP2K1, PIK3CA, PTEN, gene fusions) identify patients most likely to benefit from EGFR blockade. During treatment and at disease progression, serial ctDNA analysis detects acquired resistance mechanisms, supporting rechallenge decisions or the addition of targeted agents. This dynamic strategy integrates predictive and adaptive molecular insights to optimize anti-EGFR therapy.