Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer

Qing Zhang, Neil E. Bhola, Vivian Wai Yan Lui, Doris R. Siwak, Sufi M. Thomas, Christopher T. Gubish, Jil M. Siegfried, Gordon Mills, Dong Shin, Jennifer Rubin Grandis

Research output: Contribution to journalArticle

64 Citations (Scopus)

Abstract

Head and neck squamous cell carcinoma (HNSCC) is characterized by epidermal growth factor receptor (EGFR) overexpression, where EGFR levels correlate with survival. To date, EGFR targeting has shown limited antitumor effects in head and neck cancer when administrated as monotherapy. We previously identified a gastrin-releasing peptide/ gastrin-releasing peptide receptor (GRP/GRPR) aurocrine regulatory pathway in HNSCC, where GRP stimulates Src-dependent cleavage of EGFR proligands with subsequent EGFR phosphorylation and mitogen-activated protein kinase (MAPK) activation. To determine whether GRPR targeting can enhance the antitumor efficacy of EGFR inhibition, we investigated the effects of a GRPR antagonist (PD176252) in conjunction with an EGFR tyrosine kinase inhibitor (erlotinib). Combined blockade of GRPR and EGFR pathways significantly inhibited HNSCC, but not immortalized mucosal epithelial cell, proliferation, invasion, and colony formation. In addition, the percentage of apoptotic cells increased upon combined inhibition. The enhanced antitumor efficacy was accompanied by increased expression of cleaved poly(ADP-ribose) polymerase (PARP) and decreased phospho-EGFR, phospho-MAPK, and proliferating cell nuclear antigen (PCNA). Using reverse-phase protein microarray (RPPA), we further detected decreased expression of phospho-c-Jun, phospho-p70S6K, and phospho-p38 with combined targeting. Cumulatively, these results suggest that GRPR targeting can enhance the antitumor effects of EGFR inhibitors in head and neck cancer.

Original languageEnglish (US)
Pages (from-to)1414-1424
Number of pages11
JournalMolecular Cancer Therapeutics
Volume6
Issue number4
DOIs
StatePublished - Apr 1 2007
Externally publishedYes

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Bombesin Receptors
Head and Neck Neoplasms
Epidermal Growth Factor Receptor
Mitogen-Activated Protein Kinases
Gastrin-Releasing Peptide
70-kDa Ribosomal Protein S6 Kinases
Protein Array Analysis
Poly(ADP-ribose) Polymerases
Proliferating Cell Nuclear Antigen
Protein-Tyrosine Kinases
Epithelial Cells
Phosphorylation
Cell Proliferation

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. / Zhang, Qing; Bhola, Neil E.; Lui, Vivian Wai Yan; Siwak, Doris R.; Thomas, Sufi M.; Gubish, Christopher T.; Siegfried, Jil M.; Mills, Gordon; Shin, Dong; Grandis, Jennifer Rubin.

In: Molecular Cancer Therapeutics, Vol. 6, No. 4, 01.04.2007, p. 1414-1424.

Research output: Contribution to journalArticle

Zhang, Qing ; Bhola, Neil E. ; Lui, Vivian Wai Yan ; Siwak, Doris R. ; Thomas, Sufi M. ; Gubish, Christopher T. ; Siegfried, Jil M. ; Mills, Gordon ; Shin, Dong ; Grandis, Jennifer Rubin. / Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. In: Molecular Cancer Therapeutics. 2007 ; Vol. 6, No. 4. pp. 1414-1424.
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