HER2 expression as a potential marker for response to therapy targeted to the EGFR.
Since human epidermal growth factor receptor 2 (HER2) is known to participate with the epidermal growth factor receptor (EGFR) in mitogenic signalling, we hypothesised that HER2 overexpression might indicate responsiveness to EGFR targeted therapies. MCF7 breast cancer cells transfected with the HER2 gene were subcloned to establish a set of genetically related cell lines expressing graded levels of HER2 by immunoblot analysis. The subcloned cell lines and parental MCF7 cells were characterised by their growth characteristics, and cell by cell patterns of EGFR, HER2 and HER3 expression as well as levels of phosphorylated mitogen-activated protein kinase (MAPK) and AKT by laser scanning cytometry (LSC). Growth inhibition assays were used to characterise response to EGFR targeted therapy, and to determine the relationship between therapeutic response and levels of tyrosine kinase expression. The levels of growth inhibition of AG1478 and of the AG1478-trastuzumab combinations were correlated with levels of HER2 expression among the different cell lines. Among EGFR, HER2 and HER3, HER2 overexpression was the best single predictive marker, but combinations of two markers provided additional predictive information.
Emlet
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DR
Laboratory of Cancer Cell Biology and Genetics, Department of Human Oncology, Drexel University College of Medicine, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, PA 15212, USA.
Schwartz
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Brown
K A
KA
Pollice
A A
AA
Smith
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CA
Shackney
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D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor / Q000235:genetics*; D001943:Breast Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D047569:Laser Scanning Cytometry / Q000379:methods; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D011237:Predictive Value of Tests; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000032:analysis / Q000187:drug effects / Q000235:genetics*; D020893:Receptor, ErbB-3 / Q000032:analysis / Q000187:drug effects / Q000235:genetics; D012680:Sensitivity and Specificity; D013329:Structure-Activity Relationship; D000068878:Trastuzumab; D020032:Tyrphostins / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D014408:Biomarkers, Tumor; D066246:ErbB Receptors; D020928:Mitogen-Activated Protein Kinases; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; D000068878:Trastuzumab; D020032:Tyrphostins; C101044:RTKI cpd