El Hage Maria, Su Zhaoran, Linnebacher Michael
Molecular Oncology and Immunotherapy, Clinic of General Surgery, Rostock University Medical Center, 18057 Rostock, Germany.
Cancers (Basel). 2025 Mar 25;17(7):1098. doi: 10.3390/cancers17071098.
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.
这篇综述文章旨在探讨转移性结直肠癌（mCRC）靶向治疗所面临的挑战。我们将首先概述已获批用于治疗mCRC的靶向治疗方法，包括抗血管生成疗法，以及表皮生长因子受体（EGFR）抑制剂、BRAFV600E抑制剂、人表皮生长因子受体2（HER2）抑制剂和免疫检查点抑制剂。其次，我们将讨论原发性耐药的不同机制，包括肿瘤异质性，既有患者间异质性，也有患者内异质性，以及继发性耐药机制，包括：驱动癌基因改变、下游或平行旁路信号传导、共显性驱动癌基因的存在、肿瘤谱系可塑性以及上皮-间质转化。我们将详细讨论针对mCRC的不同药物类别所产生的耐药机制。克服耐药性的策略主要涉及联合治疗，尽管这种方法通常会增加药物毒性，表现为脱靶和非脱靶效应。此外，靶向治疗的成本和可及性给不同人群带来了重大挑战。应对这些挑战需要进一步的研究努力，以优化mCRC靶向治疗的使用。将基因组生物标志物，如测序和液体活检，整合到常规临床实践中有望改善治疗效果。总之，这篇全面的综述强调了mCRC靶向治疗中遇到的复杂挑战。
