Dienstmann Rodrigo, Salazar Ramon, Tabernero Josep
From the Sage Bionetworks, Fred Hutchinson Cancer Research Center, Seattle, WA; Medical Oncology Department, Vall d'Hebron University Hospital and Institute of Oncology, Universitat Autònoma de Barcelona, Barcelona, Spain; Department of Medical Oncology, Translational Research Laboratory, Catalan Institute of Oncology, Bellvitge Biomedical Research Institute, L'Hospitalet de Llobregat, Barcelona, Spain.
Am Soc Clin Oncol Educ Book. 2015:e149-56. doi: 10.14694/EdBook_AM.2015.35.e149.
Our understanding of the genetic and nongenetic molecular alterations associated with anti-epidermal growth factor receptor (EGFR) therapy resistance in colorectal cancer (CRC) has markedly expanded in recent years. Mutations in RAS genes (KRAS/NRAS exons 2, 3, or 4) predict a lack of clinical benefit when anti-EGFR monoclonal antibodies (mAbs) are added to chemotherapy. Genetic events in additional nodes of the mitogen-activated protein kinase (MAPK)-phosphoinositide 3-kinase (PI3K) pathways that bypass EGFR signaling, such as BRAF or PIK3CA mutations or KRAS, ERBB2, or MET amplifications, also may confer resistance to cetuximab or panitumumab. Polymorphisms that block antibody binding as a result of EGFR extracellular domain mutations have been reported. Nongenetic mechanisms, including compensatory activation of receptor tyrosine kinases HER3 and MET, together with high expression of the ligands amphiregulin, transforming growth factor alpha heregulin, and hepatocyte growth factor in the tumor microenvironment also are thought to be involved in resistance. In one-third of the samples, more than one genetic event can be found, and nongenetic events most likely coexist with gene alterations. Furthermore, activation of a gene expression signature of epithelial-mesenchymal transition has been associated with reduced cellular dependence on EGFR signaling. Collectively, this body of work provides convincing evidence that the molecular heterogeneity of CRC plays an important role in the context of resistance to anti-EGFR therapy. Herein, we discuss how this knowledge has been translated into drug development strategies to overcome primary and acquired anti-EGFR resistance, with rational combinations of targeted agents in genomically selected populations, second-generation EGFR inhibitors, and other agents expected to boost the immune response at the tumor site.
近年来，我们对与结直肠癌（CRC）抗表皮生长因子受体（EGFR）治疗耐药相关的遗传和非遗传分子改变的理解有了显著扩展。RAS基因（KRAS/NRAS外显子2、3或4）的突变预示着在化疗中添加抗EGFR单克隆抗体（mAb）时缺乏临床获益。有丝分裂原活化蛋白激酶（MAPK）-磷酸肌醇3-激酶（PI3K）通路其他节点的遗传事件，如BRAF或PIK3CA突变或KRAS、ERBB2或MET扩增，这些事件绕过EGFR信号传导，也可能导致对西妥昔单抗或帕尼单抗产生耐药。已有报道称，EGFR细胞外结构域突变导致的阻断抗体结合的多态性。非遗传机制，包括受体酪氨酸激酶HER3和MET的代偿性激活，以及肿瘤微环境中双调蛋白、转化生长因子α、神经调节蛋白和肝细胞生长因子等配体的高表达，也被认为与耐药有关。在三分之一的样本中，可以发现不止一种遗传事件，并且非遗传事件很可能与基因改变共存。此外，上皮-间质转化的基因表达特征激活与细胞对EGFR信号传导的依赖性降低有关。总的来说，这项工作提供了令人信服的证据，表明CRC的分子异质性在抗EGFR治疗耐药的背景中起着重要作用。在此，我们讨论了这些知识如何转化为药物开发策略，以克服原发性和获得性抗EGFR耐药，包括在基因组选择人群中合理联合使用靶向药物、第二代EGFR抑制剂以及其他有望增强肿瘤部位免疫反应的药物。
