Bedard Philippe L, Cardoso Fatima, Piccart-Gebhart Martine J
Department of Medical Oncology, Jules Bordet Institute, Brussels, Belgium.
J Mammary Gland Biol Neoplasia. 2009 Mar;14(1):55-66. doi: 10.1007/s10911-009-9116-x. Epub 2009 Mar 4.
Although the development of trastuzumab and lapatinib has improved the outlook for women with HER-2 positive breast cancer, resistance to HER-2 targeted therapy is a growing clinical dilemma. Recent evidence indicates that the HER-2 pathway may play an important role in the maintenance of cancer stem cells (CSCs). The success of HER-2 targeted therapies may, in part, be explained by their direct activity against HER-2 positive CSCs. Our understanding of the mechanisms involved in resistance to trastuzumab, including loss or blockade of the trastuzumab binding site, activation of alternative signaling pathways, and induction of epithelial-mesenchymal transition (EMT), suggests that CSCs may be at the root of resistance of HER-2 targeted therapy. A variety of novel HER-2 targeted approaches have demonstrated promising preliminary clinical activity. Future clinical trials should involve the integration of technologies to assess the impact of novel HER-2 targeted therapies on HER-2 positive CSCs.
尽管曲妥珠单抗和拉帕替尼的研发改善了HER-2阳性乳腺癌女性患者的预后，但对HER-2靶向治疗的耐药性是一个日益严重的临床难题。最近的证据表明，HER-2通路可能在癌症干细胞（CSCs）的维持中起重要作用。HER-2靶向治疗的成功部分可以通过其对HER-2阳性CSCs的直接活性来解释。我们对曲妥珠单抗耐药机制的理解，包括曲妥珠单抗结合位点的丧失或阻断、替代信号通路的激活以及上皮-间质转化（EMT）的诱导，表明CSCs可能是HER-2靶向治疗耐药的根源。多种新型HER-2靶向方法已显示出有前景的初步临床活性。未来的临床试验应包括整合技术，以评估新型HER-2靶向治疗对HER-2阳性CSCs的影响。
