Validation of gefitinib effectiveness in a broad panel of head and neck squamous carcinoma cells.
Recently improved understanding of the pathogenesis of human head and neck squamous cell carcinoma (HNSCC) has led to the development of new, molecular-based therapeutic strategies, one of the more promising is the utilisation of tyrosine kinase (TK) inhibitors, targeting epidermal growth factor receptor (EGFR). In this study, we tested for gefitinib effectiveness in a broad panel of 12 newly established HNSCC cell lines, investigating its ability to reduce cell growth, to induce apoptosis and to modulate cell cycle and various EGFR pathway-related targets. Gefitinib IC50 values ranged between 0.064 and 33 microM, its capability to induce apoptosis and cell accumulation in G0/G1 phase was cell line-specific, and the main EGFR-related pathway involved in gefitinib activity was PI3K/Akt/mTor. We characterised our in vitro panel extensively, with the aim to identify predictive factors for gefitinib effectiveness; all cell lines were free of human papillomavirus infection, two were positive for Fhit expression, four expressed wild-type p53, and all of them variously expressed the other two p53 family members, p63 and p73. The comparison between the targets analysed and gefitinib effectiveness evidenced the absence of a clear relationship, excluding them as predictive factors for gefitinib efficacy. Our results confirmed the in vitro efficacy of an anti-EGFR approach, but other targets than those analysed here should be characterised in order to identify valid predictive factors for gefitinib utilisation.
Sebastian
S
S
Clinical Experimental Oncology Laboratory, National Cancer Institute, Bari, Italy.
Azzariti
A
A
Accardi
R
R
Conti
D
D
Pilato
B
B
LaCalamita
R
R
Porcelli
L
L
Simone
G M
GM
Tommasi
S
S
Tommasino
M
M
Paradiso
A
A
D017766:Acid Anhydride Hydrolases / Q000235:genetics / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D015153:Blotting, Western; D002294:Carcinoma, Squamous Cell / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D016193:G1 Phase / Q000187:drug effects; D000077156:Gefitinib; D006258:Head and Neck Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D047468:Immunoprecipitation; D020128:Inhibitory Concentration 50; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology*; D016192:Resting Phase, Cell Cycle / Q000187:drug effects; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014407:Tumor Cells, Cultured; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism; D000099170:Bis(5'-adenosyl)triphosphatase
D017766:Acid Anhydride Hydrolases; D004268:DNA-Binding Proteins; D066246:ErbB Receptors; D000077156:Gefitinib; D008565:Membrane Proteins; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D000072160:Tumor Protein p73; D016159:Tumor Suppressor Protein p53; D025521:Tumor Suppressor Proteins; D000099170:Bis(5'-adenosyl)triphosphatase; C081876:CKAP4 protein, human; C000606460:TP73 protein, human