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...

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Main Authors:	Wang, Wei, Yin, Linliang, Gonzalez-Malerva, Laura, Wang, Shaopeng, Yu, Xiaobo, Eaton, Seron, Zhang, Shengtao, Chen, Hong-Yuan, LaBaer, Joshua, Tao, Nongjian
Format:	Online
Language:	English
Published:	Nature Publishing Group 2014
Online Access:	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196117/

id	pubmed-4196117
recordtype	oai_dc
spelling	pubmed-41961172014-10-21 In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance Wang, Wei Yin, Linliang Gonzalez-Malerva, Laura Wang, Shaopeng Yu, Xiaobo Eaton, Seron Zhang, Shengtao Chen, Hong-Yuan LaBaer, Joshua Tao, Nongjian Article 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. Nature Publishing Group 2014-10-14 /pmc/articles/PMC4196117/ /pubmed/25312029 http://dx.doi.org/10.1038/srep06609 Text en Copyright © 2014, Macmillan Publishers Limited. All rights reserved http://creativecommons.org/licenses/by-nc-nd/4.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License. The images or other third party material in this article are included in the article's Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder in order to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/4.0/
repository_type	Open Access Journal
institution_category	Foreign Institution
institution	US National Center for Biotechnology Information
building	NCBI PubMed
collection	Online Access
language	English
format	Online
author	Wang, Wei Yin, Linliang Gonzalez-Malerva, Laura Wang, Shaopeng Yu, Xiaobo Eaton, Seron Zhang, Shengtao Chen, Hong-Yuan LaBaer, Joshua Tao, Nongjian
spellingShingle	Wang, Wei Yin, Linliang Gonzalez-Malerva, Laura Wang, Shaopeng Yu, Xiaobo Eaton, Seron Zhang, Shengtao Chen, Hong-Yuan LaBaer, Joshua Tao, Nongjian In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
author_facet	Wang, Wei Yin, Linliang Gonzalez-Malerva, Laura Wang, Shaopeng Yu, Xiaobo Eaton, Seron Zhang, Shengtao Chen, Hong-Yuan LaBaer, Joshua Tao, Nongjian
author_sort	Wang, Wei
title	In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
title_short	In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
title_full	In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
title_fullStr	In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
title_full_unstemmed	In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
title_sort	in situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance
description	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.
publisher	Nature Publishing Group
publishDate	2014
url	https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4196117/
_version_	1613144446519476224

In situ drug-receptor binding kinetics in single cells: a quantitative label-free study of anti-tumor drug resistance

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