Cancer Research Center of Lyon, INSERM 1052/CNRS 5286/University of Lyon, Lyon, France.
Pharmacol Res Perspect. 2020 Aug;8(4):e00617. doi: 10.1002/prp2.617.
The development of targeted therapies has drastically improved the outcome of patients with different types of cancer. T-DM1 (trastuzumab-emtansine) is an antibody-drug conjugate used for the treatment of HER2-positive breast cancer combining the FDA approved mAb (monoclonal antibody) trastuzumab and the microtubule cytotoxic agent DM1 (emtansine). Despite clinical successes achieved by targeted therapies, a large number of patients develop resistance during treatment. To explore mechanisms of resistance to T-DM1, the MDA-MB-361 HER2-positive breast cancer cell line was exposed in vitro to T-DM1 in the absence or presence of ciclosporin A. Previously reported mechanisms of resistance such as trastuzumab-binding alterations, MDR1 upregulation, and SLC46A3 downregulation were not observed in these models. Despite a decrease in HER2 expression at the cell surface, both resistant cell lines remained sensitive to HER2 targeted therapies such as mAbs and tyrosine kinase inhibitors. In addition, sensitivity to DNA damaging agents and topoisomerase inhibitors were unchanged. Conversely resistance to anti-tubulin agents increased. Resistant cells displayed a decreased content of polymerized tubulin and a decreased content of βIII tubulin although the downregulation of βIII tubulin by siRNA in the parental cell line did not modified the sensitivity to T-DM1. Both cell lines resistant to T-DM1 also presented giant aneuploid cells. Several SLC (solute carrier) transporters were found to be differentially expressed in the resistant cells in comparison to parental cells. These results suggest that some characteristics such as increased baseline aneuploidy and altered intracellular drug trafficking might be involved in resistance to T-DM1.
靶向治疗的发展极大地改善了不同类型癌症患者的预后。T-DM1（曲妥珠单抗-美坦新偶联物）是一种抗体-药物偶联物，用于治疗 HER2 阳性乳腺癌，结合了 FDA 批准的 mAb（单克隆抗体）曲妥珠单抗和微管细胞毒性药物 DM1（美坦新）。尽管靶向治疗取得了临床成功，但大量患者在治疗过程中产生耐药性。为了探索对 T-DM1 耐药的机制，将 MDA-MB-361 HER2 阳性乳腺癌细胞系在体外暴露于 T-DM1 中，同时存在或不存在环孢素 A。在这些模型中没有观察到先前报道的耐药机制，如曲妥珠单抗结合改变、MDR1 上调和 SLC46A3 下调。尽管细胞表面 HER2 表达减少，但两种耐药细胞系仍然对 HER2 靶向治疗（如 mAbs 和酪氨酸激酶抑制剂）敏感。此外，对 DNA 损伤剂和拓扑异构酶抑制剂的敏感性没有改变。相反，对抗微管药物的敏感性增加。耐药细胞显示聚合微管的含量降低和βIII 微管的含量降低，尽管在亲本细胞系中用 siRNA 下调βIII 微管并未改变对 T-DM1 的敏感性。对 T-DM1 耐药的两种细胞系也表现出巨大的非整倍体细胞。与亲本细胞相比，在耐药细胞中发现了几种 SLC（溶质载体）转运体的差异表达。这些结果表明，一些特征，如基线非整倍体增加和细胞内药物转运改变，可能与对 T-DM1 的耐药性有关。
