title: Combined treatment with erlotinib and a transforming growth factor-β type I receptor inhibitor effectively suppresses the enhanced motility of erlotinib-resistant non-small-cell lung cancer cells.
abstract: BACKGROUND
  : Despite an initial dramatic response to the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, the majority of non-small cell lung cancer (NSCLC) patients with EGFR-activating mutations develop acquired resistance. Therefore, there is an urgent need to elucidate the unknown mechanisms and biological behaviors of EGFR TKI-resistant lung tumors. We investigated the motility of EGFR TKI-resistant cells, as these characteristics are relevant to cancer metastasis.
  
  
  METHODS
  : Erlotinib-resistant PC-9ER cells were generated from PC-9 NSCLC cells, which harbor an EGFR-activating mutation, and used in this study. We investigated the involvement of the transforming growth factor beta (TGF-β) pathway in cell motility, and tested the effects of erlotinib and TGF-β type I receptor (RI) inhibition on cell motility.
  
  
  RESULTS
  : PC-9ER cells displayed enhanced motility resulting from autocrine activation of the TGF-β pathway. Increased TGF-β2 secretion resulting from TGF-β2 up-regulation at the transcriptional level was suggested to be responsible for the phosphorylation of Smad2 and the subsequently elevated transcriptional regulatory activity in PC-9ER cells. The motility of PC-9ER cells was suppressed by treatment with either the TGF-βRI inhibitor LY364947 or erlotinib, and greater suppression was observed when used in combination. LY364947 or erlotinib exerted no growth-inhibitory effects, suggesting that motility and growth are driven by different signaling pathways in PC-9ER cells.
  
  
  CONCLUSIONS
  : Our results imply that blockade of the TGF-β signaling pathway combined with continuous EGFR TKI treatment will be beneficial in preventing metastasis in patients with EGFR TKI-resistant NSCLC without the EGFR T790M resistance mutation.
authors: Drug Discovery and Development Division, and †Division of Thoracic Oncology, Shizuoka Cancer Center Hospital, Shizuoka, Japan.
authors: Masakuni
authors: M
authors: Serizawa
authors: Toshiaki
authors: T
authors: Takahashi
authors: Nobuyuki
authors: N
authors: Yamamoto
authors: Yasuhiro
authors: Y
authors: Koh
mesh_terms: D015153:Blotting, Western; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D002465:Cell Movement / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D011799:Quinazolines / Q000494:pharmacology*; D012333:RNA, Messenger / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000037:antagonists & inhibitors*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D053781:Transforming Growth Factor beta2 / Q000235:genetics / Q000378:metabolism; D014407:Tumor Cells, Cultured
chemical_list: D047428:Protein Kinase Inhibitors; D011799:Quinazolines; D012333:RNA, Messenger; D018125:Receptors, Transforming Growth Factor beta; D053781:Transforming Growth Factor beta2; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D017346:Protein Serine-Threonine Kinases; D000077294:Receptor, Transforming Growth Factor-beta Type II