Compensatory Increases in Her-2/neu Activation in Response to EGFR Tyrosine Kinase Inhibition in Colon Cancer Cell Lines

Peter A. Learn, Naveen Krishnegowda, Jose Talamantez, Morton S. Kahlenberg

Research output: Contribution to journalArticlepeer-review

11 Scopus citations

Abstract

Background: Tyrosine kinase receptors of the ErbB family have become promising targets for anti-neoplastic drugs, but mechanisms of resistance are incompletely understood. To investigate such pathways, we applied a small-molecule, selective EGFR inhibitor, OSI-774, to three well-characterized colon cancer cell lines and studied the alterations of expression and activation of receptors in the erbB family. Methods: MTT assays were performed to determine the IC50s of GEO, FET, and HCT 116 human colorectal cancer cell lines treated with OSI-774. Plated cells were then exposed to either DMSO control or 7 μm of OSI-774 for treatment durations of 1, 3, 5, 7, 10, 14, 28, and 56 days. Cell lysates were evaluated by Western blotting, evaluating both total and phosphorylated levels of EGFR, Her-2/neu, and erbB-3. Results: IC50 values for GEO, FET, and HCT 116 cell lines exposed to OSI-774 were 12.0, 16.0, and greater than 100 μm, respectively. In all treated cell lines, OSI-774 diminished EGFR activation but did not affect total expression compared with controls. In contrast, Her-2/neu activation was increased in all cell lines. These changes in EGFR and Her-2/neu were identified within 24 h but peaked later in the treatment cycle. ErbB-3 expression and activation did not follow a consistent pattern between cell lines. Conclusions: Inhibition of EGFR led to increased activation of Her-2/neu. This result suggests a possible mechanism by which cells might escape the proapoptotic signals resulting from EGFR blockade. Our findings suggest concurrent inhibition of multiple members of the erbB family may yield stronger apoptotic responses than single receptor blockade alone.

Original languageEnglish (US)
Pages (from-to)227-231
Number of pages5
JournalJournal of Surgical Research
Volume136
Issue number2
DOIs
StatePublished - Dec 2006

Keywords

  • colon cancer
  • EGFR
  • Her-2/neu
  • tyrosine kinase inhibitors

ASJC Scopus subject areas

  • Surgery

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