title: Deregulated cyclin D1 expression is associated with decreased efficacy of the selective epidermal growth factor receptor tyrosine kinase inhibitor gefitinib in head and neck squamous cell carcinoma cell lines.
abstract: OBJECTIVE
  Despite promising initial results, recent Phase III trials of the selective epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor gefitinib ("Iressa"; AstraZeneca, Wilmington, Delaware) in advanced head and neck squamous cell carcinoma (HNSCC) have been equivocal. Cyclin D1, an EGFR target gene, is frequently overexpressed in HNSCC, has been implicated in its pathogenesis, and is strongly associated with poor prognosis in this disease. Therefore, we examined the relationship between deregulated cyclin D1 expression and sensitivity to gefitinib to determine whether this frequently occurring oncogenic change affected the cellular response to gefitinib.
  
  
  METHODS
  A panel of six EGFR-overexpressing HNSCC cell lines was used to correlate CCND1 gene copy number, cyclin D1 expression, and response to gefitinib. The effect of constitutive overexpression of cyclin D1 was assessed by establishing stably transfected clonal SCC-9 cell lines.
  
  
  RESULTS
  Three of six cell lines displayed cyclin D1 amplification and/or overexpression, and these cell lines were resistant to gefitinib. SCC 9 clones overexpressing cyclin D1 continued to proliferate and maintained their S-phase fraction when treated with gefitinib, whereas empty vector control clones and the parental SCC 9 cells were profoundly inhibited and displayed marked reductions in S-phase. The resistance of cyclin D1-overexpressing clones and cyclin D1-amplified cell lines was associated with maintenance of cyclin D1 expression after gefitinib treatment.
  
  
  CONCLUSIONS
  These data suggest that deregulated cyclin D1 overexpression may be associated with resistance of HNSCC to EGFR inhibitors. Therefore, the role of cyclin D1 as a marker of therapeutic response and its utility as a prognostic marker in HNSCC warrant additional analysis.
authors.affiliation: Cancer Research Program, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia.
authors.forename: Larry H
authors.initials: LH
authors.lastname: Kalish
authors.forename: Rhonda A
authors.initials: RA
authors.lastname: Kwong
authors.forename: Ian E
authors.initials: IE
authors.lastname: Cole
authors.forename: Richard M
authors.initials: RM
authors.lastname: Gallagher
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sutherland
authors.forename: Elizabeth A
authors.initials: EA
authors.lastname: Musgrove
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D015139:Blotting, Southern; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D019938:Cyclin D1 / Q000096:biosynthesis* / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D005434:Flow Cytometry; D016193:G1 Phase; D000077156:Gefitinib; D015972:Gene Expression Regulation, Neoplastic; D005822:Genetic Vectors; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D006801:Humans; D020128:Inhibitory Concentration 50; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D016196:S Phase; D013997:Time Factors
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D019938:Cyclin D1; D004247:DNA; D066246:ErbB Receptors; D000077156:Gefitinib