Yale University, School of Medicine, Department of Obstetrics, Gynecology, and Reproductive Sciences, New Haven, Connecticut, USA.
Ann N Y Acad Sci. 2010 Oct;1210:53-65. doi: 10.1111/j.1749-6632.2010.05782.x.
Trastuzumab is the first Food and Drug Administration (FDA)-approved therapeutic targeting a HER-family receptor tyrosine kinase (HER2/ErbB2/neu). Although trastuzumab is effective in the treatment of HER2-positive breast cancer, a substantial proportion of patients will not respond to trastuzumab-based regimens (primary resistance), and those who do respond will often lose clinical benefits (i.e., secondary resistance). Although multiple mechanisms underlying the development of secondary trastuzumab resistance have been identified, few studies have specifically examined the basis of primary trastuzumab resistance. Here, we review these studies, which together demonstrate that trastuzumab induces phenotypic changes in tumor cells, even when they are not growth inhibited by trastuzumab, including changes in gene expression. These changes have important clinical implications, including the sensitization of malignant cells to other therapeutic drugs. In light of these observations, we propose that the conventional definition of resistance as it pertains to trastuzumab and, perhaps, to other targeted therapeutics, may require revision. The results of these studies will be useful in informing the direction of future basic and clinical research focused on overcoming primary trastuzumab resistance.
曲妥珠单抗是首个获得美国食品药品监督管理局（FDA）批准的针对人表皮生长因子受体 2（HER2）家族受体酪氨酸激酶（HER2/ErbB2/neu）的治疗药物。尽管曲妥珠单抗在治疗 HER2 阳性乳腺癌方面非常有效，但相当一部分患者对曲妥珠单抗为基础的治疗方案没有反应（原发性耐药），而那些有反应的患者通常会失去临床获益（即继发性耐药）。尽管已经确定了继发性曲妥珠单抗耐药的多种机制，但很少有研究专门研究原发性曲妥珠单抗耐药的基础。在这里，我们回顾了这些研究，这些研究共同表明，曲妥珠单抗即使不能抑制肿瘤细胞的生长，也会诱导肿瘤细胞发生表型变化，包括基因表达的变化。这些变化具有重要的临床意义，包括使恶性细胞对其他治疗药物敏感。鉴于这些观察结果，我们提出，传统上关于曲妥珠单抗（也许还有其他靶向治疗药物）耐药的定义可能需要修改。这些研究的结果将有助于为未来针对克服原发性曲妥珠单抗耐药的基础和临床研究指明方向。
