Leite Luís Felipe, Noronha Mariana Macambira, de Menezes Junior Samuel Alonso, da Conceição Lucas Diniz, Almeida Luiz F Costa, Cappellaro Anelise Poluboiarinov, Belotto Marcos, Biachi de Castria Tiago, Peixoto Renata D'Alpino, Megid Thais Baccili Cury
Department of Medical Sciences, Universidade Federal Fluminense, Niteroi 24220-140, RJ, Brazil.
Department of Medical Sciences, Universidade Federal do Ceará, Fortaleza 60020-181, CE, Brazil.
Cancers (Basel). 2025 Aug 27;17(17):2804. doi: 10.3390/cancers17172804.
Epidermal growth factor receptor (EGFR) inhibitors remain a cornerstone in the treatment of metastatic colorectal cancer with and 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 (HER2) and , 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 and 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.
表皮生长因子受体（EGFR）抑制剂仍然是治疗具有KRAS和NRAS野生型癌症的转移性结直肠癌的基石。然而，原发性和获得性耐药限制了它们对许多患者的益处。越来越多的证据表明，耐药并非随机发生，而是由维持肿瘤生长独立于EGFR信号传导的复杂分子改变网络驱动。这些改变包括HER2和NRAS的扩增、PI3K和AKT途径的激活、EGFR细胞外结构域突变以及罕见的激酶融合。阴性超选择的概念已成为一种强大的策略，通过排除具有这些耐药驱动因素的肿瘤来优化患者选择。多项临床试验一致表明，与仅根据KRAS和NRAS状态选择的患者相比，基于全面分子谱分析进行超选择的患者实现了显著更高的缓解率和更长的生存期。通过循环肿瘤DNA进行液体活检进一步改变了这一局面，提供了一种非侵入性工具来捕捉肿瘤异质性、实时监测克隆进化，并在耐药出现后指导重新挑战策略。总之，阴性超选择、ctDNA引导的监测和新兴疗法为识别、追踪和克服mCRC中抗EGFR治疗的耐药性定义了一个精准肿瘤学框架，推动该领域朝着更有效和个性化的治疗发展。展望未来，双特异性抗体、抗体药物偶联物和基于RNA的疗法等创新疗法的开发有望在这一具有挑战性的临床场景中进一步扩展。这些进展将结直肠癌的精准肿瘤学从概念转变为临床现实，通过分子洞察重塑治疗标准。
