In Situ Drug-Receptor Binding Kinetics in Single Cells: A Quantitative Label-Free Study of Anti-Tumor Drug Resistance
Many drugs are effective in the early stage of treatment, but patients develop drug resistance after a certain period of treatment, causing failure of the therapy. An important example is Herceptin, a popular monoclonal antibody drug for breast cancer by specifically targeting human epidermal growth factor receptor 2 (Her2). Here we demonstrate a quantitative binding kinetics analysis of drug-target interactions to investigate the molecular scale origin of drug resistance. Using a surface plasmon resonance imaging, we measured the in situ Herceptin-Her2 binding kinetics in single intact cancer cells for the first time, and observed significantly weakened Herceptin-Her2 interactions in Herceptin-resistant cells, compared to those in Herceptin-sensitive cells. We further showed that the steric hindrance of Mucin-4, a membrane protein, was responsible for the altered drug-receptor binding. This effect of a third molecule on drug-receptor interactions cannot be studied using traditional purified protein methods, demonstrating the importance of the present intact cell-based binding kinetics analysis.
- Author (aut): Wang, Wei
- Author (aut): Yin, Linliang
- Author (aut): Gonzalez-Malerva, Laura
- Author (aut): Wang, Shaopeng
- Author (aut): Yu, Xiaobo
- Author (aut): Eaton, Seron
- Author (aut): Zhang, Shengtao
- Author (aut): Chen, Hong-Yuan
- Author (aut): LaBaer, Joshua
- Author (aut): Tao, Nongjian
- Contributor (ctb): Biodesign Institute