Institute of Clinical Medicine, University of Oslo, Oslo, Norway.
Department of Pathology, Oslo University Hospital, Oslo, Norway.
J Cell Mol Med. 2020 Sep;24(17):10258-10262. doi: 10.1111/jcmm.15643. Epub 2020 Jul 16.
The receptor tyrosine kinase HER2 is associated with a number of human malignancies and is an important therapeutic target. The antibody-drug conjugate trastuzumab emtansine (T-DM1; Kadcyla ) is recommended as a first-line treatment for patients with HER2-positive metastatic breast cancer. T-DM1 combines the antibody-induced effects of the anti-HER2 antibody trastuzumab (Herceptin ) with the cytotoxic effect of the tubulin inhibitor mertansine (DM1). For DM1 to have effect, the T-DM1-HER2 complex has to be internalized and the trastuzumab part of T-DM1 has to be degraded. HER2 is, however, considered endocytosis-resistant. As a result of this, trastuzumab is only internalized to a highly limited extent, and if internalized, it is rapidly recycled. The exact reasons for the endocytosis resistance of HER2 are not clear, but it is stabilized by heat-shock protein 90 (Hsp90) and Hsp90 inhibitors induce internalization and degradation of HER2. HER2 can also be internalized upon activation of protein kinase C, and contrary to trastuzumab alone, the combination of two or more anti-HER2 antibodies can induce efficient internalization and degradation of HER2. With intention to find ways to improve the action of T-DM1, we investigated how different ways of inducing HER2 internalization leads to degradation of trastuzumab. The results show that although both Hsp90 inhibition and activation of protein kinase C induce internalization of trastuzumab, only Hsp90 inhibition induces degradation. Furthermore, we find that antibody internalization and degradation are increased when trastuzumab is combined with the clinically approved anti-HER2 antibody pertuzumab (Perjeta ).
受体酪氨酸激酶 HER2 与多种人类恶性肿瘤相关，是一个重要的治疗靶点。抗体药物偶联物曲妥珠单抗-美坦新（T-DM1；Kadcyla）被推荐用于治疗 HER2 阳性转移性乳腺癌患者的一线治疗药物。T-DM1 结合了抗 HER2 抗体曲妥珠单抗（赫赛汀）的抗体诱导作用和微管蛋白抑制剂美坦新（DM1）的细胞毒性作用。为了使 DM1 发挥作用，T-DM1-HER2 复合物必须被内化，并且 T-DM1 的曲妥珠单抗部分必须被降解。然而，HER2 被认为是内吞抵抗的。因此，曲妥珠单抗仅被内化到非常有限的程度，如果被内化，它会迅速被回收。HER2 内吞抵抗的确切原因尚不清楚，但它被热休克蛋白 90（Hsp90）稳定，Hsp90 抑制剂诱导 HER2 的内化和降解。HER2 也可以在蛋白激酶 C 激活时被内化，并且与单独使用曲妥珠单抗相反，两种或更多种抗 HER2 抗体的组合可以诱导 HER2 的有效内化和降解。为了寻找提高 T-DM1 作用的方法，我们研究了不同诱导 HER2 内化的方法如何导致曲妥珠单抗的降解。结果表明，尽管 Hsp90 抑制和蛋白激酶 C 激活都诱导曲妥珠单抗内化，但只有 Hsp90 抑制诱导降解。此外，我们发现当曲妥珠单抗与临床批准的抗 HER2 抗体 pertuzumab（Perjeta）联合使用时，抗体内化和降解增加。
