Antitumor mechanisms of combined gastrin-releasing peptide receptor and epidermal growth factor receptor targeting in head and neck cancer.
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.
Zhang
Qing
Q
Department of Pharmacology, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
Bhola
Neil E
NE
Lui
Vivian Wai Yan
VW
Siwak
Doris R
DR
Thomas
Sufi M
SM
Gubish
Christopher T
CT
Siegfried
Jill M
JM
Mills
Gordon B
GB
Shin
Dong
D
Grandis
Jennifer Rubin
JR
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D014408:Biomarkers, Tumor / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D000069347:Erlotinib Hydrochloride; D016193:G1 Phase / Q000187:drug effects; D006258:Head and Neck Neoplasms / Q000188:drug therapy / Q000473:pathology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D009361:Neoplasm Invasiveness; D011799:Quinazolines / Q000494:pharmacology*; D018004:Receptors, Bombesin / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects; D014410:Tumor Stem Cell Assay
D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; D011799:Quinazolines; D018004:Receptors, Bombesin; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; C116774:PD 176252