Combined inhibition of c-Src and epidermal growth factor receptor abrogates growth and invasion of head and neck squamous cell carcinoma.
OBJECTIVE
Increased expression and/or activation of epidermal growth factor receptor (EGFR) is associated with tumor progression and poor prognosis in many cancers, including head and neck squamous cell carcinoma (HNSCC). Src family kinases, including c-Src, mediate a variety of intracellular or extracellular signals that contribute to tumor formation and progression. This study was undertaken to elucidate the role of c-Src in the growth and invasion of HNSCC and to determine the effects of combined targeting of EGFR and Src kinases in HNSCC cell lines.


METHODS
HNSCC cells were engineered to stably express a dominant-active form of c-Src and investigated in cell growth and invasion assays. The biochemical effects of combined treatment with the Src inhibitor AZD0530, a potent, orally active Src inhibitor with Bcr/Abl activity, and the EGFR kinase inhibitor gefitinib were examined, as well as the consequences of dual Src/EGFR targeting on the growth and invasion of a panel of HNSCC cell lines.


RESULTS
HNSCC cells expressing dominant-active c-Src showed increased growth and invasion compared with vector-transfected controls. Combined treatment with AZD0530 and gefitinib resulted in greater inhibition of HNSCC cell growth and invasion compared with either agent alone.


CONCLUSIONS
These results suggest that increased expression and activation of c-Src promotes HNSCC progression where combined targeting of EGFR and c-Src may be an efficacious treatment approach.
Koppikar
Priya
P
Department of Otolaryngology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania, USA
Choi
Seung-Ho
SH
Egloff
Ann Marie
AM
Cai
Quan
Q
Suzuki
Shinsuke
S
Freilino
Maria
M
Nozawa
Hiroshi
H
Thomas
Sufi M
SM
Gooding
William E
WE
Siegfried
Jill M
JM
Grandis
Jennifer R
JR
D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018450:Disease Progression; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D015972:Gene Expression Regulation, Neoplastic; D016391:Genes, src; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism*; D006801:Humans; D020128:Inhibitory Concentration 50; D009361:Neoplasm Invasiveness; D010766:Phosphorylation; D011379:Prognosis; D019061:src-Family Kinases / Q000037:antagonists & inhibitors*
D066246:ErbB Receptors; D019061:src-Family Kinases