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 journalArticle

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
Externally publishedYes

Fingerprint

Head and Neck Neoplasms
Epidermal Growth Factor Receptor
Proteomics
Signal Transduction
Survival
STAT3 Transcription Factor
Protein Array Analysis
Biomarkers
Tumor Cell Line
Inhibitory Concentration 50
Enzyme-Linked Immunosorbent Assay
Proto-Oncogene Proteins c-akt
Mitogen-Activated Protein Kinase 3
gefitinib
Mitogen-Activated Protein Kinase 1
Bromides
Pharmaceutical Preparations
Carcinoma, squamous cell of head and neck
Research Design
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer. / Pernas, Francisco G.; Allen, Clint T; Winters, Mary E.; Yan, Bin; Friedman, Jay; Dabir, Bhavana; Saigal, Kunal; Mundinger, Gerhard S.; Xu, Xiaojiang; Morris, John C.; Calvo, Katherine R.; Van Waes, Carter; Chen, Zhong.

In: Clinical Cancer Research, Vol. 15, No. 7, 01.04.2009, p. 2361-2372.

Research output: Contribution to journalArticle

Pernas, FG, Allen, CT, Winters, ME, Yan, B, Friedman, J, Dabir, B, Saigal, K, Mundinger, GS, Xu, X, Morris, JC, Calvo, KR, Van Waes, C & Chen, Z 2009, 'Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer', Clinical Cancer Research, vol. 15, no. 7, pp. 2361-2372. https://doi.org/10.1158/1078-0432.CCR-08-1011
Pernas, Francisco G. ; Allen, Clint T ; Winters, Mary E. ; Yan, Bin ; Friedman, Jay ; Dabir, Bhavana ; Saigal, Kunal ; Mundinger, Gerhard S. ; Xu, Xiaojiang ; Morris, John C. ; Calvo, Katherine R. ; Van Waes, Carter ; Chen, Zhong. / Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer. In: Clinical Cancer Research. 2009 ; Vol. 15, No. 7. pp. 2361-2372.
@article{f7851ba1ab3240afbf46c63fc8f46945,
title = "Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer",
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.",
author = "Pernas, {Francisco G.} and Allen, {Clint T} and Winters, {Mary E.} and Bin Yan and Jay Friedman and Bhavana Dabir and Kunal Saigal and Mundinger, {Gerhard S.} and Xiaojiang Xu and Morris, {John C.} and Calvo, {Katherine R.} and {Van Waes}, Carter and Zhong Chen",
year = "2009",
month = "4",
day = "1",
doi = "10.1158/1078-0432.CCR-08-1011",
language = "English (US)",
volume = "15",
pages = "2361--2372",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research Inc.",
number = "7",

}

TY - JOUR

T1 - Proteomic signatures of epidermal growth factor receptor and survival signal pathways correspond to gefitinib sensitivity in head and neck cancer

AU - Pernas, Francisco G.

AU - Allen, Clint T

AU - Winters, Mary E.

AU - Yan, Bin

AU - Friedman, Jay

AU - Dabir, Bhavana

AU - Saigal, Kunal

AU - Mundinger, Gerhard S.

AU - Xu, Xiaojiang

AU - Morris, John C.

AU - Calvo, Katherine R.

AU - Van Waes, Carter

AU - Chen, Zhong

PY - 2009/4/1

Y1 - 2009/4/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=65349130024&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=65349130024&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-08-1011

DO - 10.1158/1078-0432.CCR-08-1011

M3 - Article

C2 - 19318490

AN - SCOPUS:65349130024

VL - 15

SP - 2361

EP - 2372

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 7

ER -