Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells

BMC Cancer

Research Article

Sajjad M. Soltani¹  Abhijit Dandapat¹  David J. Burns¹  Yao Huang¹  Benjamin E. Rich¹  Samantha Myhre¹  Brian F. Sullivan¹  Ian A. MacNeil¹  Lance G. Laing¹  Leo T. Furcht²  Carol A. Lange³ 

[1] Celcuity LLC, Minneapolis, MN, USA;Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA;Division of Hematology, Oncology, and Transplantation, Departments of Medicine and Pharmacology and The Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA;

关键词: CELx HSF Test;    Cancer diagnostic;    HER2-negative;    HER2-positive;    Breast cancer;    Signaling pathway;    Targeted therapeutics;    Oncology;    Breast tumor;    Primary epithelial cells;   

DOI  :  10.1186/s12885-017-3181-0

 received in 2016-08-03, accepted in 2017-03-08,  发布年份 2017

来源: Springer

【 摘 要 】

BackgroundApproximately 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.MethodsA new biosensor-based test (CELxTM 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.ResultsThe 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.ConclusionsMeasurement 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.

【 授权许可】

CC BY   
© The Author(s). 2017