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 B. Mills, Dong Shin, Jennifer Rubin Grandis

Research output: Contribution to journalArticle

66 Scopus citations

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

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Fingerprint Dive into the research topics of 'Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer'. Together they form a unique fingerprint.

  • Cite this

    Zhang, Q., Bhola, N. E., Lui, V. W. Y., Siwak, D. R., Thomas, S. M., Gubish, C. T., Siegfried, J. M., Mills, G. B., Shin, D., & Grandis, J. R. (2007). Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer. Molecular cancer therapeutics, 6(4), 1414-1424. https://doi.org/10.1158/1535-7163.MCT-06-0678