Translational Cancer Medicine Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland.
Institute for Molecular Medicine FIMM and EV Core, University of Helsinki, Helsinki, Finland.
Mol Cancer Ther. 2019 Oct;18(10):1721-1730. doi: 10.1158/1535-7163.MCT-19-0207. Epub 2019 Jul 10.
Most patients with HER2-positive breast or gastric cancer exhibit primary or acquired resistance to trastuzumab emtansine (T-DM1), and such patients may have limited therapeutic options. XMT-1522 is a novel anti-HER2 antibody-drug conjugate. We compared XMT-1522 to T-DM1 in preclinical models. The effects of XMT-1522 and T-DM1 on cell survival and apoptosis were compared in six HER2-positive breast cancer or gastric cancer cell lines, of which three lines were T-DM1-sensitive (N-87, OE-19, JIMT-1) and three T-DM1-resistant (RN-87, ROE-19, SNU-216). We compared these agents also in the HER2-negative breast cancer cell line MCF-7, and in mouse RN-87 and JIMT-1 xenograft models. Cell survival was assessed using the AlamarBlue method and apoptosis with the Caspase-Glo 3/7 method. XMT-1522 inhibited the growth of all six HER2-positive cell lines. The proportions of cells that survived XMT-1522 treatment were smaller as compared with T-DM1, particularly in the T-DM1-resistant cell lines. XMT-1522 induced more cell apoptosis compared with T-DM1. While RN-87 and JIMT-1 xenograft tumors progressed on T-DM1 treatment, all tumors responded to XMT-1522, and all but one tumor disappeared during the XMT-1522 treatment. XMT-1522 had a strong antitumor effect on RN-87 and JIMT-1 xenografts that progressed on T-DM1. We conclude that XMT-1522 was effective in HER2-positive breast cancer and gastric cancer cell lines resistant to T-DM1, and in xenograft models resistant to T-DM1. The results support the testing of XMT-1522 in clinical trials in patients with HER2-positive cancer.
大多数 HER2 阳性乳腺癌或胃癌患者对曲妥珠单抗emtansine（T-DM1）表现出原发性或获得性耐药，此类患者的治疗选择可能有限。XMT-1522 是一种新型抗 HER2 抗体-药物偶联物。我们在临床前模型中比较了 XMT-1522 与 T-DM1 的疗效。在六种 HER2 阳性乳腺癌或胃癌细胞系中比较了 XMT-1522 和 T-DM1 对细胞存活和凋亡的影响，其中三种细胞系对 T-DM1 敏感（N-87、OE-19、JIMT-1），三种细胞系对 T-DM1 耐药（RN-87、ROE-19、SNU-216）。我们还在 HER2 阴性乳腺癌细胞系 MCF-7 中和在携带 RN-87 和 JIMT-1 的荷瘤小鼠模型中比较了这些药物。用 AlamarBlue 法评估细胞存活，用 Caspase-Glo 3/7 法评估细胞凋亡。XMT-1522 抑制了所有六种 HER2 阳性细胞系的生长。与 T-DM1 相比，XMT-1522 处理后存活的细胞比例更小，尤其是在 T-DM1 耐药细胞系中。XMT-1522 诱导的细胞凋亡比 T-DM1 更多。尽管 T-DM1 治疗使 RN-87 和 JIMT-1 异种移植瘤进展，但所有肿瘤均对 XMT-1522 有反应，且在 XMT-1522 治疗期间除一个肿瘤外，所有肿瘤均消失。XMT-1522 对 T-DM1 耐药的 RN-87 和 JIMT-1 异种移植瘤具有很强的抗肿瘤作用。我们得出结论，XMT-1522 对 T-DM1 耐药的 HER2 阳性乳腺癌和胃癌细胞系以及对 T-DM1 耐药的异种移植瘤有效。这些结果支持在 HER2 阳性癌症患者中进行 XMT-1522 的临床试验。
