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

Yao Huang, David J. Burns, Benjamin E. Rich, Ian A. MacNeil, Abhijit Dandapat, Sajjad M. Soltani, Samantha Myhre, Brian F. Sullivan, Carol A. Lange, Leo T. Furcht, Lance G. Laing

Research output: Contribution to journalArticle

7 Scopus citations

Abstract

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 (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. 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.

Original languageEnglish (US)
Article number199
JournalBMC Cancer
Volume17
Issue number1
DOIs
StatePublished - Mar 16 2017

Keywords

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

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    Huang, Y., Burns, D. J., Rich, B. E., MacNeil, I. A., Dandapat, A., Soltani, S. M., Myhre, S., Sullivan, B. F., Lange, C. A., Furcht, L. T., & Laing, L. G. (2017). Development of a test that measures real-time HER2 signaling function in live breast cancer cell lines and primary cells. BMC Cancer, 17(1), [199]. https://doi.org/10.1186/s12885-017-3181-0