Diessner J, Bruttel V, Stein R G, Horn E, Häusler S F M, Dietl J, Hönig A, Wischhusen J
Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
1] Department for Obstetrics and Gynecology, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany [2] Else-Kröner Research Training Program for Clinician Scientists, University of Würzburg Medical School, Josef-Schneider-Street 4, Würzburg 97080, Germany.
Cell Death Dis. 2014 Mar 27;5(3):e1149. doi: 10.1038/cddis.2014.115.
The antibody trastuzumab (Herceptin) has substantially improved overall survival for patients with aggressive HER2-positive breast cancer. However, about 70% of all treated patients will experience relapse or disease progression. This may be related to an insufficient targeting of the CD44(high)CD24(low) breast cancer stem cell subset, which is not only highly resistant to chemotherapy and radiotherapy but also a poor target for trastuzumab due to low HER2 surface expression. Hence, we explored whether the new antibody-drug conjugate T-DM1, which consists of the potent chemotherapeutic DM1 coupled to trastuzumab, could improve the targeting of these tumor-initiating or metastasis-initiating cells. To this aim, primary HER2-overexpressing tumor cells as well as HER2-positive and HER2-negative breast cancer cell lines were treated with T-DM1, and effects on survival, colony formation, gene and protein expression as well as antibody internalization were assessed. This revealed that CD44(high)CD24(low)HER2(low) stem cell-like breast cancer cells show high endocytic activity and are thus particularly sensitive towards the antibody-drug conjugate T-DM1. Consequently, preexisting CD44(high)CD24(low) cancer stem cells were depleted by concentrations of T-DM1 that did not affect the bulk of the tumor cells. Likewise, colony formation was efficiently suppressed. Moreover, when tumor cells were cocultured with natural killer cells, antibody-dependent cell-mediated cytotoxicity was enhanced, and EMT-mediated induction of stem cell-like properties was prevented in differentiated tumor cells. Thus our study reveals an unanticipated targeting of stem cell-like breast cancer cells by T-DM1 that may contribute to the clinical efficacy of this recently approved antibody-drug conjugate.
抗体曲妥珠单抗（赫赛汀）显著提高了侵袭性HER2阳性乳腺癌患者的总生存率。然而，所有接受治疗的患者中约70%会出现复发或疾病进展。这可能与CD44（高）CD24（低）乳腺癌干细胞亚群的靶向不足有关，该亚群不仅对化疗和放疗具有高度抗性，而且由于HER2表面表达低，也是曲妥珠单抗的不良靶点。因此，我们探讨了由强效化疗药物DM1与曲妥珠单抗偶联而成的新型抗体药物偶联物T-DM1是否能改善对这些肿瘤起始或转移起始细胞的靶向作用。为此，用T-DM1处理原发性HER2过表达肿瘤细胞以及HER2阳性和HER2阴性乳腺癌细胞系，并评估其对细胞存活、集落形成、基因和蛋白表达以及抗体内化的影响。结果显示，CD44（高）CD24（低）HER2（低）干细胞样乳腺癌细胞具有高内吞活性，因此对抗体药物偶联物T-DM1特别敏感。因此，不影响大部分肿瘤细胞的T-DM1浓度可耗尽预先存在的CD44（高）CD24（低）癌干细胞。同样，集落形成也得到有效抑制。此外，当肿瘤细胞与自然杀伤细胞共培养时，抗体依赖性细胞介导的细胞毒性增强，并且在分化的肿瘤细胞中可防止EMT介导的干细胞样特性诱导。因此，我们的研究揭示了T-DM1对干细胞样乳腺癌细胞的意外靶向作用，这可能有助于这种最近获批的抗体药物偶联物的临床疗效。
