title: Synergistic inhibition of ErbB signaling by combined treatment with seliciclib and ErbB-targeting agents.
abstract: OBJECTIVE
  The aims of this study were to investigate whether the cyclin-dependent kinase inhibitor seliciclib could synergize with agents that target ErbB receptors and to elucidate the molecular mechanism of the observed synergy.
  
  
  METHODS
  Synergy between seliciclib and ErbB receptor targeted agents was investigated in various cell lines using the Calcusyn median effect model. The molecular mechanism of the observed synergy was studied in cultured cells, and the combination of seliciclib and the epidermal growth factor receptor (EGFR) inhibitor erlotinib was evaluated in an H358 xenograft model.
  
  
  RESULTS
  Seliciclib synergized with the anti-HER2 antibody trastuzumab in a breast cancer cell line, which overexpresses the HER2 receptor, and with the erlotinib analogue AG1478 in non-small cell lung cancer cell lines. In the H358 non-small cell lung cancer cell line, synergy involved decreased signaling from the EGFR, with AG1478 directly inhibiting kinase activity while seliciclib decreased the levels of key components of the receptor signaling pathway, resulting in enhanced loss of phosphorylated extracellular signal-regulated kinase and cyclin D1. The combination of seliciclib and erlotinib was evaluated further in an H358 xenograft and shown to be significantly more active than either agent alone. An enhanced loss of cyclin D1 was also seen in vivo.
  
  
  CONCLUSIONS
  This is the first report that investigates combining seliciclib with an EGFR inhibitor. The combination decreased signaling from the EGFR in vitro and in vivo and was effective in cell lines containing either wild-type or mutant EGFR, suggesting that it may expand the range of tumors that respond to erlotinib, and therefore, such combinations are worth exploring in the clinic.
authors.affiliation: Cyclacel Ltd., Dundee, United Kingdom. ifleming@cyclacel.com
authors.forename: Ian N
authors.initials: IN
authors.lastname: Fleming
authors.forename: Morag
authors.initials: M
authors.lastname: Hogben
authors.forename: Sheelagh
authors.initials: S
authors.lastname: Frame
authors.forename: Steven J
authors.initials: SJ
authors.lastname: McClue
authors.forename: Simon R
authors.initials: SR
authors.lastname: Green
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D019938:Cyclin D1 / Q000378:metabolism; D004357:Drug Synergism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020128:Inhibitory Concentration 50; D051379:Mice; D008954:Models, Biological; D009154:Mutation; D009368:Neoplasm Transplantation; D011687:Purines / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077546:Roscovitine
chemical_list: D000970:Antineoplastic Agents; D019938:Cyclin D1; D011687:Purines; D018719:Erb-b2 Receptor Tyrosine Kinases; D000077546:Roscovitine