Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer

Francisco G. Pernas, Clint T. Allen, Mary E. Winters, Bin Yan, Jay Friedman, Bhavana Dabir, Kunal Saigal, Gerhard S. Mundinger, Xiaojiang Xu, John C. Morris, Katherine R. Calvo, Carter Van Waes, Zhong Chen

Research output: Contribution to journalArticlepeer-review

Abstract

Purpose: Gefitinib targeting of the epidermal growth factor receptor (EGFR) has shown limited activity in clinical trials of head and neck squamous cell carcinoma (HNSCC). To investigate the underlying molecular mechanism, the proteomic signatures and responses of EGFR and downstream signals have been studied in a panel of HNSCC cell lines and tumor specimens pre- and post-gefitinib treatment. Experimental Design: The IC50 of gefitinib for HNSCC cell lines were determined using 3-(4,5- dmethylthiazol-2-yl) -2,5-diphenyltetrazolium bromide proliferation assay. The effects of gefitinib on activation of EGFR and downstream signaling molecules were determined by Western blot, ELISA, and reverse-phase protein microarray (RPMA). The biomarkers involved in the signaling pathways were examined in HNSCC tumor specimens from patients in a phase I gefitinib trial. Results: In vitro, gefitinib inhibited cell proliferation with differing IC50, and suppressed activation of EGFR and downstream signaling molecules protein kinase B (AKT), extracellular signal- regulated kinase 1/2, signal transducer and activator of transcription 3 (STAT3), and nuclear factor κB. The drug sensitivity was statistically correlated with activation of phosphorylated AKT (p-AKT) and phosphorylated STAT3 (p-STAT3) detected by ELISA, and consistent with results measured by RPMA. In patient samples, a broad suppression of activation of EGFR and downstream signaling molecules was observed in a molecular responder patient, in contrast to a lack of inhibition or increased activation of biomarkers in different pathways in nonresponder patients. Conclusions: Gefitinib sensitivity is correlated with p-AKT and p-STAT3 activation in HNSCC cell lines and tumor specimens. p-AKT and p-STAT3 could serve as potentially useful biomarkers and drug targets for further development of novel therapeutic agents for HNSCC.

Original languageEnglish (US)
Pages (from-to)2361-2372
Number of pages12
JournalClinical Cancer Research
Volume15
Issue number7
DOIs
StatePublished - Apr 1 2009

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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