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 in vitro 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. Mol Cancer Ther; 17(7); 1441–53. ©2018 AACR.

中文翻译：

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乳腺癌细胞对曲妥珠单抗 Emtansine 获得性耐药的机制

受体酪氨酸激酶 HER2 在大约 20% 的乳腺癌中过度表达，其扩增与存活率降低有关。Trastuzumab emtansine (Kadcyla, T-DM1) 是一种抗体-药物偶联物，由曲妥珠单抗通过稳定接头与抗有丝分裂剂 DM1 共价连接而成，旨在选择性地将 DM1 递送至过度表达 HER2 的肿瘤细胞。T-DM1 被批准用于治疗曲妥珠单抗和紫杉类药物进展后的 HER2 阳性转移性乳腺癌患者。尽管临床结果有所改善，但许多最初对 T-DM1 治疗有反应的患者最终发展为疾病进展。导致 T-DM1 抗性的机制尚不完全清楚。为此，我们开发了 T-DM1 抗性体外模型来检查获得性 T-DM1 抗性的机制。我们证明 HER2 的减少和 MDR1 的上调有助于 KPL-4 T-DM1 抗性细胞中的 T-DM1 抗性。相比之下，SLC46A3 的缺失和 PTEN 缺陷都在赋予 BT-474M1 T-DM1 抗性细胞抗性中起作用。我们的数据表明这两种细胞系通过不同的机制获得抗性。此外，我们表明 KPL-4 T-DM1 抗性可以通过用 MDR1 抑制剂治疗来克服，而 PI3K 抑制剂可以挽救 T-DM1 抗性 BT-474M1 细胞中 PTEN 缺失诱导的抗性。我们的研究结果为开发治疗策略以通过将 T-DM1 和其他靶向信号转导或抗性途径的抑制剂相结合来增强 T-DM1 临床疗效提供了理论依据。摩尔癌症治疗; 17(7); 1441-53。©2018 AACR。