Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer withRASandBRAFwild-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 ofERBB2(HER2) andMET, 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 byRASandBRAFstatus 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.
表皮生长因子受体（EGFR）抑制剂仍是治疗RAS与BRAF野生型转移性结直肠癌的基石。然而，原发性和获得性耐药限制了其对许多患者的疗效。越来越多的证据表明，耐药并非随机发生，而是由复杂的分子改变网络驱动，这些改变使肿瘤生长不再依赖EGFR信号通路。这些机制包括ERBB2（HER2）和MET基因扩增、PI3K与AKT通路激活、EGFR胞外域突变以及罕见激酶融合。负向超选择概念已成为优化患者选择的重要策略，通过排除携带这些耐药驱动因素的肿瘤来实现。多项临床试验一致表明，基于全面分子谱分析进行超选择的患者，相较于仅依据RAS和BRAF状态选择的患者，可获得显著更高的缓解率和更长的生存期。基于循环肿瘤DNA的液体活检进一步改变了这一格局，为捕捉肿瘤异质性、实时监测克隆演化、指导耐药后再挑战策略提供了无创工具。负向超选择、ctDNA引导的监测以及新兴疗法共同构建了mCRC抗EGFR治疗耐药识别、追踪与克服的精准肿瘤学框架，推动该领域迈向更有效、个体化的诊疗。展望未来，双特异性抗体、抗体药物偶联物及RNA疗法等创新药物的研发，有望在这一充满挑战的临床场景中进一步拓展。这些进展正推动结直肠癌精准肿瘤学从概念走向临床现实，通过分子层面的深刻洞察重塑治疗标准。
Anti-EGFR Therapy in Metastatic Colorectal Cancer: Identifying, Tracking, and Overcoming Resistance
肿瘤(癌症)患者之家