Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, 300 E 66th Street, New York, NY 10065, USA.
Expert Rev Anticancer Ther. 2011 Feb;11(2):263-75. doi: 10.1586/era.10.226.
HER2 amplification is seen in up to 20% of breast cancers and is associated with an aggressive phenotype. Trastuzumab, a monoclonal antibody to HER2, accrues significant clinical benefit in the metastatic and adjuvant settings. However, some patients suffer disease recurrence despite adjuvant trastuzumab therapy, and many patients with metastatic disease do not respond to therapy or develop refractory disease within 1 year of treatment. Given the increased recognition of de novo and acquired resistance to therapy, considerable research has been dedicated to understanding the molecular mechanisms of trastuzumab resistance. Here, we highlight putative models of resistance, including activation of the downstream PI3K-signaling pathway, accumulation of a constitutively active form of HER2, and crosstalk of HER2 with other growth factor receptors. The identification of these specific mechanisms of trastuzumab resistance has provided a rationale for the development of several novel HER2-targeted agents as the mechanisms have largely suggested a continued tumor dependence on HER2 signaling. We explore the emerging data for the treatment of trastuzumab-refractory disease with novel agents including lapatinib, neratinib, pertuzumab, trastuzumab-DM1, HSP90 and PI3K pathway inhibitors, and the future potential for these inhibitors which, if combined with reliable biomarkers of resistance, may ultimately usher in a new era of personalized medicine for this disease.
HER2 扩增见于多达 20%的乳腺癌病例中，与侵袭性表型相关。曲妥珠单抗，一种针对 HER2 的单克隆抗体，在转移性和辅助治疗环境中带来显著的临床获益。然而，尽管接受了辅助曲妥珠单抗治疗，一些患者仍会出现疾病复发，许多转移性疾病患者在治疗后 1 年内对治疗无反应或出现难治性疾病。鉴于对治疗的新发和获得性耐药的认识不断提高，大量研究致力于理解曲妥珠单抗耐药的分子机制。在这里，我们强调了耐药的假设模型，包括下游 PI3K 信号通路的激活、HER2 持续激活形式的积累，以及 HER2 与其他生长因子受体的串扰。这些曲妥珠单抗耐药的特定机制的鉴定为几种新型 HER2 靶向药物的开发提供了依据，因为这些机制在很大程度上表明肿瘤仍然依赖 HER2 信号。我们探讨了新型药物（包括拉帕替尼、奈拉替尼、帕妥珠单抗、曲妥珠单抗-DM1、HSP90 和 PI3K 通路抑制剂）治疗曲妥珠单抗耐药疾病的最新数据，以及这些抑制剂的未来潜力，如果与耐药的可靠生物标志物相结合，可能最终为这种疾病带来新的个体化医疗时代。
