期刊
CANCERS
卷 12, 期 3, 页码 -出版社
MDPI
DOI: 10.3390/cancers12030670
关键词
breast cancer; HER2; antibody-drug conjugate; SYD985; T-DM1; patient-derived xenograft
类别
资金
- Breast Cancer Research Foundation [BCRF-19-08]
- Fundacion Mutua Madrilena, Instituto de Salud Carlos III [AC15/00062]
- EC - FEDER, Instituto de Salud Carlos III [CB16/12/00449, PI19/01181]
- Asociacion Espanola Contra el Cancer
- PERIS (Departament de Salut, Generalitat de Catalunya)
- China Scholarship Council (CSC)
- Institucio Catalana de Recerca i Estudis Avancats
Trastuzumab-emtansine (T-DM1) is an antibody-drug conjugate (ADC) approved for the treatment of HER2 (human epidermal growth factor receptor 2)-positive breast cancer. T-DM1 consists of trastuzumab covalently linked to the cytotoxic maytansinoid DM1 via a non-cleavable linker. Despite its efficacy, primary or acquired resistance frequently develops, particularly in advanced stages of the disease. Second generation ADCs targeting HER2 are meant to supersede T-DM1 by using a cleavable linker and a more potent payload with a different mechanism of action. To determine the effect of one of these novel ADCs, SYD985, on tumors resistant to T-DM1, we developed several patient-derived models of resistance to T-DM1. Characterization of these models showed that previously described mechanisms-HER2 downmodulation, impairment of lysosomal function and upregulation of drug efflux pumps-account for the resistances observed, arguing that mechanisms of resistance to T-DM1 are limited, and most of them have already been described. Importantly, SYD985 was effective in these models, showing that the resistance to first generation ADCs can be overcome with an improved design.
作者
我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。
推荐
暂无数据