Department of Biochemistry and Molecular Medicine, UC Davis NCI-designated Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
Department of Radiation Oncology, School of Medicine, University of California Davis, Sacramento, CA, USA.
Nat Nanotechnol. 2020 Feb;15(2):145-153. doi: 10.1038/s41565-019-0626-4. Epub 2020 Jan 27.
Human epidermal growth factor receptor 2 (HER2) is overexpressed in >20% of breast cancers. Dimerization of HER2 receptors leads to the activation of downstream signals enabling the proliferation and survival of malignant phenotypes. Owing to the high expression levels of HER2, combination therapies are currently required for the treatment of HER2 breast cancer. Here, we designed non-toxic transformable peptides that self-assemble into micelles under aqueous conditions but, on binding to HER2 on cancer cells, transform into nanofibrils that disrupt HER2 dimerization and subsequent downstream signalling events leading to apoptosis of cancer cells. The phase transformation of peptides enables specific HER2 targeting, and inhibition of HER2 dimerization blocks the expression of proliferation and survival genes in the nucleus. We demonstrate, in mouse xenofraft models, that these transformable peptides can be used as a monotherapy in the treatment of HER2 breast cancer.
人类表皮生长因子受体 2(HER2)在超过 20%的乳腺癌中过表达。HER2 受体的二聚化导致下游信号的激活,从而促进恶性表型的增殖和存活。由于 HER2 的高表达水平,目前需要联合治疗来治疗 HER2 乳腺癌。在这里,我们设计了非毒性可变形肽,在水相条件下自组装成胶束,但在与癌细胞上的 HER2 结合后,转化为纳米纤维,破坏 HER2 二聚化和随后的下游信号事件,导致癌细胞凋亡。肽的相转变使 HER2 能够特异性靶向,并抑制核内增殖和存活基因的表达。我们在小鼠异种移植模型中证明,这些可变形肽可作为单一疗法用于治疗 HER2 乳腺癌。