Department of Translational Oncology, Genentech, Inc., South San Francisco, California.
Department of Preclinical and Translational Pharmacokinetics, Genentech, Inc., South San Francisco, California.
Mol Cancer Ther. 2018 Jul;17(7):1441-1453. doi: 10.1158/1535-7163.MCT-17-0296. Epub 2018 Apr 25.
The receptor tyrosine kinase HER2 is overexpressed in approximately 20% of breast cancer, and its amplification is associated with reduced survival. Trastuzumab emtansine (Kadcyla, T-DM1), an antibody-drug conjugate that is comprised of trastuzumab covalently linked to the antimitotic agent DM1 through a stable linker, was designed to selectively deliver DM1 to HER2-overexpressing tumor cells. T-DM1 is approved for the treatment of patients with HER2-positive metastatic breast cancer following progression on trastuzumab and a taxane. Despite the improvement in clinical outcome, many patients who initially respond to T-DM1 treatment eventually develop progressive disease. The mechanisms that contribute to T-DM1 resistance are not fully understood. To this end, we developed T-DM1-resistant models to examine the mechanisms of acquired T-DM1 resistance. We demonstrate that decreased HER2 and upregulation of MDR1 contribute to T-DM1 resistance in KPL-4 T-DM1-resistant cells. In contrast, both loss of SLC46A3 and PTEN deficiency play a role in conferring resistance in BT-474M1 T-DM1-resistant cells. Our data suggest that these two cell lines acquire resistance through distinct mechanisms. Furthermore, we show that the KPL-4 T-DM1 resistance can be overcome by treatment with an inhibitor of MDR1, whereas a PI3K inhibitor can rescue PTEN loss-induced resistance in T-DM1-resistant BT-474M1 cells. Our results provide a rationale for developing therapeutic strategies to enhance T-DM1 clinical efficacy by combining T-DM1 and other inhibitors that target signaling transduction or resistance pathways. .
受体酪氨酸激酶 HER2 在大约 20%的乳腺癌中过表达，其扩增与生存降低有关。曲妥珠单抗-美坦新偶联物（Kadcyla，T-DM1）是一种抗体-药物偶联物，由通过稳定连接子共价连接的曲妥珠单抗和抗有丝分裂剂 DM1 组成，旨在将 DM1 选择性递送至 HER2 过表达的肿瘤细胞。T-DM1 获批用于治疗曲妥珠单抗和紫杉烷治疗后进展的 HER2 阳性转移性乳腺癌患者。尽管临床结局有所改善，但许多最初对 T-DM1 治疗有反应的患者最终仍会发生疾病进展。导致 T-DM1 耐药的机制尚未完全阐明。为此，我们开发了 T-DM1 耐药模型来研究获得性 T-DM1 耐药的机制。我们证明，HER2 减少和 MDR1 上调有助于 KPL-4 T-DM1 耐药细胞中的 T-DM1 耐药。相比之下，SLC46A3 的缺失和 PTEN 缺陷都在 BT-474M1 T-DM1 耐药细胞中发挥作用，导致耐药。我们的数据表明，这两种细胞系通过不同的机制获得耐药性。此外，我们表明，MDR1 抑制剂可克服 KPL-4 T-DM1 耐药性，而 PI3K 抑制剂可挽救 T-DM1 耐药性 BT-474M1 细胞中 PTEN 缺失引起的耐药性。我们的研究结果为通过联合 T-DM1 和其他靶向信号转导或耐药途径的抑制剂来提高 T-DM1 临床疗效提供了一种合理的治疗策略。
