Järvinen Tero A H, Liu Edison T
Burnham Institute for Medical Research, La Jolla, CA 92037, USA.
Curr Cancer Drug Targets. 2006 Nov;6(7):579-602. doi: 10.2174/156800906778742497.
The HER-2 (also known as ERBB2/ErbB2/c-erbB2/HER-2/neu) oncogene is the most frequently amplified oncogene in breast cancer and is also amplified in other forms of cancer. Beside its important role in tumor induction, growth and progression, HER-2 is also a target for new therapeutic approaches such as Herceptin (trastuzumab), a recombinant antibody designed to block signaling through the HER-2 receptor. In addition to Herceptin, which is in a wide clinical use for HER-2 amplified breast cancer, a number of various HER-2 directed immunological and genetic strategies, either targeting the HER-2 receptor, its signaling pathways or both HER-2 and epidermal growth factor receptor (EGFR) simultaneously, have demonstrated promising pre-clinical activity in HER-2 amplified carcinomas. Moreover, the HER-2 amplicon is known to contain more than 30 genes with altered copy numbers that could be therapeutic targets for chemotherapy. The topoisomerase IIalpha gene, TOP2A, is located adjacent to the HER-2 oncogene at the chromosome location 17q12-q21 and is either amplified or deleted (with equal frequency) in a great majority of HER-2 amplified primary breast tumors and also in tumors without HER-2 amplification. Recent experimental as well as numerous, large, multi-center trials suggest that amplification (and/or deletion) of TOP2A may account for both sensitivity or resistance to commonly used cytotoxic drugs, i.e. topoII-inhibitors (anthracyclines etc.), depending on the specific genetic defect at the TOP2A locus. The understanding of HER-2 amplification and its role in the pathogenesis of cancer is expanding, and a number of therapeutic strategies targeting either the HER-2 or its signaling pathways in cancer therapy are being investigated. Combining HER-2 targeting therapies with conventional forms of cytotoxic chemotherapy, where additional diagnostic tests such as those ascertaining TOP2A status, may be helpful for the ideal selection of patients for the combination therapy of an HER-2 targeting drug together with a cytotoxic drug such as topoII-inhibitor especially in the case of TOP2A amplification.
HER-2（也称为ERBB2/ErbB2/c-erbB2/HER-2/neu）癌基因是乳腺癌中最常扩增的癌基因，在其他癌症形式中也会扩增。除了在肿瘤诱导、生长和进展中起重要作用外，HER-2还是新治疗方法的靶点，如赫赛汀（曲妥珠单抗），一种旨在阻断通过HER-2受体信号传导的重组抗体。除了在HER-2扩增的乳腺癌中广泛临床应用的赫赛汀外，一些针对HER-2的各种免疫和基因策略，无论是靶向HER-2受体、其信号通路还是同时靶向HER-2和表皮生长因子受体（EGFR），在HER-2扩增的癌中都显示出有前景的临床前活性。此外，已知HER-2扩增子包含30多个拷贝数改变的基因，这些基因可能是化疗的治疗靶点。拓扑异构酶IIα基因（TOP2A）位于染色体17q12-q21位置，与HER-2癌基因相邻，在大多数HER-2扩增的原发性乳腺癌以及无HER-2扩增的肿瘤中，该基因要么扩增要么缺失（频率相同）。最近的实验以及众多大型多中心试验表明，TOP2A的扩增（和/或缺失）可能导致对常用细胞毒性药物（即拓扑异构酶II抑制剂，如蒽环类药物等）的敏感性或耐药性，这取决于TOP2A基因座的特定基因缺陷。对HER-2扩增及其在癌症发病机制中的作用的理解正在不断扩展，并且正在研究许多针对癌症治疗中HER-2或其信号通路的治疗策略。将HER-2靶向治疗与传统形式的细胞毒性化疗相结合，其中额外的诊断测试（如确定TOP2A状态的测试）可能有助于理想地选择患者进行HER-2靶向药物与细胞毒性药物（如拓扑异构酶II抑制剂）联合治疗，特别是在TOP2A扩增的情况下。
