TGF-β and Cancer Group, Oncobell Program, Bellvitge Biomedical Research Institute (IDIBELL), Barcelona, Spain; National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBERehd), Instituto de Salud Carlos III, Madrid, Spain; Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
Sorbonne Université, Inserm, Centre de Recherche Saint-Antoine (CRSA), Paris, France.
Drug Resist Updat. 2022 Sep;64:100863. doi: 10.1016/j.drup.2022.100863. Epub 2022 Aug 27.
The Epidermal Growth Factor Receptor (EGFR) has been targeted through the development of selective tyrosine kinase inhibitors (TKIs) and monoclonal antibodies (mAb). These molecules have shown effectiveness in a subset of patients with specific genetic alterations (i.e. gain-of-function EGFR mutations or EGFR gene amplification) and have been approved for their use in non-small-cell lung cancer (NSCLC), colorectal cancer (CRC), pancreatic cancer and head and neck cancer. In addition, extensive research is being performed in many other tumour types hoping for a future approval. However, the majority of the patients show no benefit from these molecules due to primary mechanisms of resistance, already present before treatment or show disease progression upon the acquisition of drug resistance mechanisms during the treatment. At present, the majority of patients display resistance due to alterations in genes related to the EGFR signalling pathway that eventually circumvent EGFR inhibition and allow cancer progression. Thus, in this review article we focus on the molecular mechanisms underlying drug resistance via genetic alterations leading to resistance to all anti-EGFR drugs approved by the FDA and/or EMA. We also discuss novel approaches to surmount these chemoresistance modalities.
表皮生长因子受体（EGFR）已通过开发选择性酪氨酸激酶抑制剂（TKIs）和单克隆抗体（mAb）进行靶向治疗。这些分子在具有特定遗传改变（即功能获得性 EGFR 突变或 EGFR 基因扩增）的特定患者亚组中显示出有效性，并已被批准用于非小细胞肺癌（NSCLC）、结直肠癌（CRC）、胰腺癌和头颈部癌症。此外，许多其他肿瘤类型正在进行广泛的研究，希望未来能够获得批准。然而，由于存在原发性耐药机制，大多数患者并未从这些分子中获益，这些机制在治疗前就已经存在，或者在治疗过程中获得耐药机制时出现疾病进展。目前，大多数患者由于与 EGFR 信号通路相关的基因改变而产生耐药性，这些改变最终绕过 EGFR 抑制作用并允许癌症进展。因此，在这篇综述文章中，我们重点讨论了导致对 FDA 和/或 EMA 批准的所有抗 EGFR 药物产生耐药性的遗传改变相关的耐药性分子机制。我们还讨论了克服这些化疗耐药模式的新方法。
