title: High cyclin D3 expression confers erlotinib resistance in aerodigestive tract cancer.
abstract: BACKGROUND
  Prior studies highlighted cyclin D1 as a key biomarker of response to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors. This study builds on prior work by examining the roles of cyclin D1, cyclin D3, and cyclin E in mediating erlotinib sensitivity or resistance.
  
  
  METHODS
  Expression plasmids for G1 cyclins were independently transfected into NIH 3T3 cells and effects on erlotinib sensitivity were examined. The expression profiles of G1 cyclins were compared in erlotinib-sensitive and erlotinib-resistant lung cancer cell lines. A549 and H358 cells were treated with erlotinib and changes in cyclin protein expression were assessed. Cyclin D3 immunohistochemical staining was measured in biopsy tissues obtained from patients before and after treatment with erlotinib. Erlotinib-sensitive lung cancer cells were transfected with cyclin D3 and changes in erlotinib sensitivity were examined.
  
  
  RESULTS
  Individual transfection of cyclin D1, cyclin D3, and cyclin E expression plasmids each significantly reduced erlotinib sensitivity in NIH-3T3 cells. The erlotinib-resistant A549 cell line expressed high basal levels of cyclin D3 mRNA and protein. Comparison of tumor biopsies obtained from patients before and after treatment with erlotinib indicated an increase in the percentage of cancer cells expressing cyclin D3 following treatment with erlotinib (P=.02). Transfection of cyclin D3 into an erlotinib-sensitive lung cancer cell line inhibited erlotinib-induced signaling changes and reduced the growth-suppressive effects of erlotinib.
  
  
  CONCLUSIONS
  High expression of cyclin D3 confers resistance to erlotinib in vitro and in vivo. Cyclin D3 immunohistochemical staining warrants investigation as a biomarker for predicting erlotinib resistance.
authors.affiliation: Department of Medicine, Wake Forest University Health Sciences, Winston-Salem, NC, USA. wpetty@wfubmc.edu
authors.forename: W Jeffrey
authors.initials: WJ
authors.lastname: Petty
authors.forename: William R
authors.initials: WR
authors.lastname: Voelzke
authors.forename: James J
authors.initials: JJ
authors.lastname: Urbanic
authors.forename: Victor A
authors.initials: VA
authors.lastname: Varela
authors.forename: Lynsay L
authors.initials: LL
authors.lastname: Waller
authors.forename: Catherine B
authors.initials: CB
authors.lastname: Swift
authors.forename: R Matthew
authors.initials: RM
authors.lastname: Graham
authors.forename: Vincent A
authors.initials: VA
authors.lastname: Memoli
authors.forename: Konstantin H
authors.initials: KH
authors.lastname: Dragnev
mesh_terms: D000818:Animals; D054316:Biomarkers, Pharmacological / Q000378:metabolism; D002277:Carcinoma / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D019938:Cyclin D1 / Q000235:genetics / Q000378:metabolism; D056743:Cyclin D3 / Q000235:genetics / Q000378:metabolism; D019927:Cyclin E / Q000235:genetics / Q000378:metabolism; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D005770:Gastrointestinal Neoplasms / Q000175:diagnosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D041681:NIH 3T3 Cells; D011799:Quinazolines / Q000494:pharmacology / Q000627:therapeutic use*
chemical_list: D054316:Biomarkers, Pharmacological; D056743:Cyclin D3; D019927:Cyclin E; D011799:Quinazolines; D019938:Cyclin D1; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors