title: Effect of dasatinib on EMT-mediated-mechanism of resistance against EGFR inhibitors in lung cancer cells.
abstract: The epithelial to mesenchymal transition (EMT) is associated with acquired resistance to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) in certain non-small cell lung cancers that harbor EGFR mutations. Because no currently available drugs specifically kill cancer cells via EMT, novel treatment strategies that overcome or prevent EMT are needed. A recent report suggested that dasatinib (an ABL/Src kinase inhibitor) inhibits EMT induced by transforming growth factor (TGF)-beta in lung cancer cells (Wilson et al., 2014). In this study, we analyzed effects of dasatinib on the resistance mechanism in HCC4006 cells, which tend to acquire resistance to EGFR-TKIs via EMT.
  
  
  
  Sensitivity to dasatinib in HCC4006 and HCC4006 erlotinib-resistant (ER) cells with an EMT phenotype was analyzed. HCC4006 cells acquired resistance against the combination of erlotinib and dasatinib (HCC4006EDR) following chronic treatment with these drugs. The expression of EMT markers and the resistance mechanism were analyzed.
  
  
  
  Short-term or long-term treatment with dasatinib did not reverse EMT in HCC4006ER. In contrast, HCC4006EDR cells maintained an epithelial phenotype, and the mechanism underlying resistance to erlotinib plus dasatinib combination therapy was attributable to a T790M secondary mutation. HCC4006EDR cells, but not HCC4006ER cells, were highly sensitive to a third-generation EGFR-TKI, osimertinib.
  
  
  
  Although dasatinib monotherapy did not reverse EMT in HCC4006ER cells, preemptive combination treatment with erlotinib and dasatinib prevented the emergence of acquired resistance via EMT, and led to the emergence of T790M. Our results indicate that preemptive combination therapy may be a promising strategy to prevent the emergence of EMT-mediated resistance.
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Sesumi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Suda
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Mizuuchi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Yoshihisa
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Katsuaki
authors.initials: K
authors.lastname: Sato
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Masato
authors.initials: M
authors.lastname: Chiba
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Masaki
authors.initials: M
authors.lastname: Shimoji
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Tomizawa
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan.
authors.forename: Toshiki
authors.initials: T
authors.lastname: Takemoto
authors.affiliation: Division of Thoracic Surgery, Department of Surgery, Kindai University Faculty of Medicine, 377-2 Ohno-Higashi, Osaka-Sayama, 589-8511, Japan. Electronic address: mitsudom@surg.med.kindai.ac.jp.
authors.forename: Tetsuya
authors.initials: T
authors.lastname: Mitsudomi
mesh_terms: D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor / Q000187:drug effects* / Q000378:metabolism; D000069439:Dasatinib / Q000494:pharmacology*; D019008:Drug Resistance, Neoplasm; D004359:Drug Therapy, Combination / Q000379:methods; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects* / Q000235:genetics; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000235:genetics; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D009154:Mutation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D016896:Treatment Outcome
chemical_list: D047428:Protein Kinase Inhibitors; D000069347:Erlotinib Hydrochloride; C512478:EGFR protein, human; D066246:ErbB Receptors; D000069439:Dasatinib
keywords: Acquired resistance; Dasatinib; Epithelial-mesenchymal transition; Non-small cell lung cancer; Third- generation EGFR-TKI