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Effects of trastuzumab and afatinib on kinase activity in gastric cancer cell lines.
Mol. Oncol. 12, 441-462 (2018)
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The molecular mechanism of action of the HER2-targeted antibody trastuzumab is only partially understood, and the direct effects of trastuzumab on the gastric cancer signaling network are unknown. In this study, we compared the molecular effect of trastuzumab and the HER kinase inhibitor afatinib on the receptor tyrosine kinase (RTK) network and the downstream-acting intracellular kinases in gastric cancer cell lines. The molecular effects of trastuzumab and afatinib on the phosphorylation of 49 RTKs and 43 intracellular kinase phosphorylation sites were investigated in three gastric cancer cell lines (NCI-N87, MKN1, and MKN7) using proteome profiling. To evaluate these effects, data were analyzed using mixed models and clustering. Moreover, proliferation assays were performed. Our comprehensive quantitative analysis of kinase activity in gastric cancer cell lines indicates that trastuzumab and afatinib selectively influenced the HER family RTKs. The effects of trastuzumab differed between cell lines, depending on the presence of activated HER2. The effects of trastuzumab monotherapy were not transduced to the intracellular kinase network. Afatinib alone or in combination with trastuzumab influenced HER kinases in all cell lines; that is, the effects of monotherapy and combination therapy were transduced to the intracellular kinase network. These results were confirmed by proliferation analysis. Additionally, the MET-amplified cell line Hs746T was identified as afatinib nonresponder. The dependence of the effect of trastuzumab on the presence of activated HER2 might explain the clinical nonresponse of some patients who are routinely tested for HER2 expression and gene amplification in the clinic but not for HER2 activation. The consistent effects of afatinib on HER RTKs and downstream kinase activation suggest that afatinib might be an effective candidate in the future treatment of patients with gastric cancer irrespective of the presence of activated HER2. However, MET amplification should be taken into account as potential resistance factor.
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Publication type
Article: Journal article
Document type
Scientific Article
Keywords
Afatinib ; Gastric Cancer ; Her2 ; Kinase Activity ; Proteome Profiler ; Trastuzumab
Language
Publication Year
2018
HGF-reported in Year
2018
ISSN (print) / ISBN
1574-7891
e-ISSN
1878-0261
Journal
Molecular Oncology
Quellenangaben
Volume: 12,
Issue: 4,
Pages: 441-462
Publisher
Elsevier
Publishing Place
Amsterdam [u.a.]
Reviewing status
Peer reviewed
Institute(s)
Institute of Computational Biology (ICB)
POF-Topic(s)
30205 - Bioengineering and Digital Health
Research field(s)
Enabling and Novel Technologies
PSP Element(s)
G-553800-001
Scopus ID
85045112483
PubMed ID
29325228
Erfassungsdatum
2018-01-31