Novel Targeted Therapies to Overcome Trastuzumab Resistance in HER2-Overexpressing Metastatic Breast Cancer
Novel Targeted Therapies to Overcome Trastuzumab Resistance in HER2-Overexpressing Metastatic Breast Cancer
复制标题
克服 HER2 过表达转移性乳腺癌曲妥珠单抗耐药性的新型靶向疗法
DOI：
10.2174/13894501113149990161
复制
发表时间：
2013-07-01
影响因子：
3.2
通讯作者：
Fan, Weimin
中科院分区：
文献类型：
--
作者：
Huang, Yuan;Fu, Peifen;Fan, Weimin
人表皮生长因子受体2（HER 2）的过表达在大约25-30%的乳腺癌中被鉴定，并且指示不良预后。曲妥珠单抗，抗HER 2单克隆抗体（mAb），已显示出显着的临床效果，选择性地在HER 2过表达转移性乳腺癌（MBC）与改善总生存期和降低复发风险。然而，迫切需要开发新的策略来克服先天性和获得性曲妥珠单抗耐药性，这已经越来越多地发生。近年来，对曲妥珠单抗耐药机制的认识不断加深，极大地促进了曲妥珠单抗难治性疾病新型靶向治疗的发展。据信，涉及人表皮生长因子受体（EGFR/HER）家族、磷酸肌醇3激酶/Akt（PI 3 K/Akt）通路和血管内皮生长因子（VEGF）家族的几种信号通路的异常激活有助于曲妥珠单抗耐药性的发展。针对这些相关信号通路的新型药物提供了一些潜在的解决方案，如酪氨酸激酶抑制剂（TKI）和mAb。HER 2也被认为是免疫学靶点。不能诱导免疫介导的抗肿瘤应答是曲妥珠单抗耐药的另一个重要原因。增强T细胞介导的HER 2特异性免疫应答的策略，包括HER 2疫苗和双特异性抗体（bsAb），可以被开发为预防复发或对抗曲妥珠单抗耐药性的有希望的方法。在这篇综述中，将讨论与这些新疗法相关的临床前和临床研究的新数据。
Overexpression of the human epidermal growth factor receptor 2 (HER2) is identified in approximately 25-30% of breast cancers and indicates a poor prognosis. Trastuzumab, the anti-HER2 monoclonal antibody (mAb), has shown significant clinical effects selectively in HER2-overexpressing metastatic breast cancer (MBC) with improved overall survival and reduced recurrent risk. However, there is an urgent need to develop new strategies to overcome innate and acquired trastuzumab resistance, which has increasingly occurred. Recently, an increased understanding of mechanisms of trastuzumab resistance significantly promotes the development of novel targeted therapies for trastuzumab-refractory disease. It is believed that aberrant activations of several signaling pathways involving the human epidermal growth factor receptor (EGFR/HER) family, phosphoinositide 3 kinase/Akt (PI3K/Akt) pathway, and vascular endothelial growth factor (VEGF) family, contribute to the development of trastuzumab resistance. Novel agents that target these relevant signal pathways provide some potential solutions, such as tyrosine kinase inhibitors (TKIs) and mAbs. HER2 is also recognized as an immunotherapeutic target. The failure to induce immune-mediated antitumor response is another important reason for trastuzumab resistance. Strategies to boost T cell-mediated immune responses specific to HER2 including HER2 vaccines and bispecific antibodies (bsAbs) could be developed as a promising way to prevent relapse or combat trastuzumab resistance. In this review, the emerging data from preclinical and clinical studies related to these novel therapies will be discussed.