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Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells
BACKGROUND: Approximately 18–20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have foun...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2017
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356237/ https://www.ncbi.nlm.nih.gov/pubmed/28302091 http://dx.doi.org/10.1186/s12885-017-3181-0 |
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author | Huang, Yao Burns, David J. Rich, Benjamin E. MacNeil, Ian A. Dandapat, Abhijit Soltani, Sajjad M. Myhre, Samantha Sullivan, Brian F. Lange, Carol A. Furcht, Leo T. Laing, Lance G. |
author_facet | Huang, Yao Burns, David J. Rich, Benjamin E. MacNeil, Ian A. Dandapat, Abhijit Soltani, Sajjad M. Myhre, Samantha Sullivan, Brian F. Lange, Carol A. Furcht, Leo T. Laing, Lance G. |
author_sort | Huang, Yao |
collection | PubMed |
description | BACKGROUND: Approximately 18–20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2. This suggests that measurement of other biological factors associated with HER2 cancer, such as HER2 signaling pathway activity, should be considered as an alternative means of identifying patients eligible for HER2 therapies. METHODS: A new biosensor-based test (CELx(TM) HSF) that measures HER2 signaling activity in live cells is demonstrated using a set of 19 human HER2+ and HER2– breast cancer reference cell lines and primary cell samples derived from two fresh patient tumor specimens. Pathway signaling is elucidated by use of highly specific agonists and antagonists. The test method relies upon well-established phenotypic, adhesion-related, impedance changes detected by the biosensor. RESULTS: The analytical sensitivity and analyte specificity of this method was demonstrated using ligands with high affinity and specificity for HER1 and HER3. The HER2-driven signaling quantified ranged 50-fold between the lowest and highest cell lines. The HER2+ cell lines were almost equally divided into high and low signaling test result groups, suggesting that little correlation exists between HER2 protein expression and HER2 signaling level. Unexpectedly, the highest HER2-driven signaling level recorded was with a HER2– cell line. CONCLUSIONS: Measurement of HER2 signaling activity in the tumor cells of breast cancer patients is a feasible approach to explore as a biomarker to identify HER2-driven cancers not currently diagnosable with genomic techniques. The wide range of HER2-driven signaling levels measured suggests it may be possible to make a distinction between normal and abnormal levels of activity. Analytical validation studies and clinical trials treating HER2- patients with abnormal HER2-driven signaling would be required to evaluate the analytical and clinical validity of using this functional biomarker as a diagnostic test to select patients for treatment with HER2 targeted therapy. In clinical practice, this method would require patient specimens be delivered to and tested in a central lab. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-017-3181-0) contains supplementary material, which is available to authorized users. |
format | Online Article Text |
id | pubmed-5356237 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2017 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-53562372017-03-22 Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells Huang, Yao Burns, David J. Rich, Benjamin E. MacNeil, Ian A. Dandapat, Abhijit Soltani, Sajjad M. Myhre, Samantha Sullivan, Brian F. Lange, Carol A. Furcht, Leo T. Laing, Lance G. BMC Cancer Research Article BACKGROUND: Approximately 18–20% of all human breast cancers have overexpressed human epidermal growth factor receptor 2 (HER2). Standard clinical practice is to treat only overexpressed HER2 (HER2+) cancers with targeted anti-HER2 therapies. However, recent analyses of clinical trial data have found evidence that HER2-targeted therapies may benefit a sub-group of breast cancer patients with non-overexpressed HER2. This suggests that measurement of other biological factors associated with HER2 cancer, such as HER2 signaling pathway activity, should be considered as an alternative means of identifying patients eligible for HER2 therapies. METHODS: A new biosensor-based test (CELx(TM) HSF) that measures HER2 signaling activity in live cells is demonstrated using a set of 19 human HER2+ and HER2– breast cancer reference cell lines and primary cell samples derived from two fresh patient tumor specimens. Pathway signaling is elucidated by use of highly specific agonists and antagonists. The test method relies upon well-established phenotypic, adhesion-related, impedance changes detected by the biosensor. RESULTS: The analytical sensitivity and analyte specificity of this method was demonstrated using ligands with high affinity and specificity for HER1 and HER3. The HER2-driven signaling quantified ranged 50-fold between the lowest and highest cell lines. The HER2+ cell lines were almost equally divided into high and low signaling test result groups, suggesting that little correlation exists between HER2 protein expression and HER2 signaling level. Unexpectedly, the highest HER2-driven signaling level recorded was with a HER2– cell line. CONCLUSIONS: Measurement of HER2 signaling activity in the tumor cells of breast cancer patients is a feasible approach to explore as a biomarker to identify HER2-driven cancers not currently diagnosable with genomic techniques. The wide range of HER2-driven signaling levels measured suggests it may be possible to make a distinction between normal and abnormal levels of activity. Analytical validation studies and clinical trials treating HER2- patients with abnormal HER2-driven signaling would be required to evaluate the analytical and clinical validity of using this functional biomarker as a diagnostic test to select patients for treatment with HER2 targeted therapy. In clinical practice, this method would require patient specimens be delivered to and tested in a central lab. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (doi:10.1186/s12885-017-3181-0) contains supplementary material, which is available to authorized users. BioMed Central 2017-03-16 /pmc/articles/PMC5356237/ /pubmed/28302091 http://dx.doi.org/10.1186/s12885-017-3181-0 Text en © The Author(s). 2017 Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. |
spellingShingle | Research Article Huang, Yao Burns, David J. Rich, Benjamin E. MacNeil, Ian A. Dandapat, Abhijit Soltani, Sajjad M. Myhre, Samantha Sullivan, Brian F. Lange, Carol A. Furcht, Leo T. Laing, Lance G. Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title | Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title_full | Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title_fullStr | Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title_full_unstemmed | Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title_short | Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells |
title_sort | development of a test that measures real-time her2 signaling function in live breast cancer cell lines and primary cells |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5356237/ https://www.ncbi.nlm.nih.gov/pubmed/28302091 http://dx.doi.org/10.1186/s12885-017-3181-0 |
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