Rexer Brent N, Arteaga Carlos L
Departments of Medicine and Cancer Biology, Breast Cancer Research Program, Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37212, USA.
Crit Rev Oncog. 2012;17(1):1-16. doi: 10.1615/critrevoncog.v17.i1.20.
Approximately 25% of human breast cancers overexpress the HER2 (ErbB2) proto-oncogene, which confers a more aggressive tumor phenotype and associates with a poor prognosis in patients with this disease. Two approved therapies targeting HER2, the monoclonal antibody trastuzumab and the tyrosine kinase inhibitor lapatinib, are clinically active against this type of breast cancer. However, a significant fraction of patients with HER2+ breast cancer treated with these agents eventually relapse or develop progressive disease. This suggests that tumors acquire or possess intrinsic mechanisms of resistance that allow escape from HER2 inhibition. This review focuses on mechanisms of intrinsic and/or acquired resistance to HER2-targeted therapies that have been identified in preclinical and clinical studies. These mechanisms involve alterations to HER2 itself, coexpression or acquisition of bypass signaling through other receptor or intracellular signaling pathways, defects in mechanisms of cell cycle regulation or apoptosis, and host factors that may modulate drug response. Emerging clinical evidence already suggests that combinations of therapies targeting HER2 as well as these resistance pathways will be effective in overcoming or preventing resistance.
大约25%的人类乳腺癌过度表达HER2（ErbB2）原癌基因，这赋予肿瘤更具侵袭性的表型，并与该疾病患者的不良预后相关。两种获批的靶向HER2的疗法，单克隆抗体曲妥珠单抗和酪氨酸激酶抑制剂拉帕替尼，对这类乳腺癌具有临床活性。然而，接受这些药物治疗的HER2阳性乳腺癌患者中有很大一部分最终会复发或病情进展。这表明肿瘤获得或具有内在的耐药机制，从而能够逃避HER2抑制。本综述重点关注在临床前和临床研究中已确定的对HER2靶向治疗的内在和/或获得性耐药机制。这些机制包括HER2自身的改变、通过其他受体或细胞内信号通路共表达或获得旁路信号、细胞周期调控或凋亡机制的缺陷，以及可能调节药物反应的宿主因素。新出现的临床证据已经表明，靶向HER2以及这些耐药途径的联合疗法将有效克服或预防耐药。
