title: EGF Induced RET Inhibitor Resistance in CCDC6-RET Lung Cancer Cells.
abstract: OBJECTIVE
  Rearrangement of the proto-oncogene rearranged during transfection (RET) has been newly identified potential driver mutation in lung adenocarcinoma. Clinically available tyrosine kinase inhibitors (TKIs) target RET kinase activity, which suggests that patients with RET fusion genes may be treatable with a kinase inhibitor. Nevertheless, the mechanisms of resistance to these agents remain largely unknown. Thus, the present study aimed to determine whether epidermal growth factor (EGF) and hepatocyte growth factor (HGF) trigger RET inhibitor resistance in LC-2/ad cells with CCDC6-RET fusion genes.
  
  
  METHODS
  The effects of EGF and HGF on the susceptibility of a CCDC6-RET lung cancer cell line to RET inhibitors (sunitinib, E7080, vandetanib, and sorafenib) were examined.
  
  
  RESULTS
  CCDC6-RET lung cancer cells were highly sensitive to RET inhibitors. EGF activated epidermal growth factor receptor (EGFR) and triggered resistance to sunitinib, E7080, vandetanib, and sorafenib by transducing bypass survival signaling through ERK and AKT. Reversible EGFR-TKI (gefitinib) resensitized cancer cells to RET inhibitors, even in the presence of EGF. Endothelial cells, which are known to produce EGF, decreased the sensitivity of CCDC6-RET lung cancer cells to RET inhibitors, an effect that was inhibited by EGFR small interfering RNA (siRNA), anti-EGFR antibody (cetuximab), and EGFR-TKI (Iressa). HGF had relatively little effect on the sensitivity to RET inhibitors.
  
  
  CONCLUSIONS
  EGF could trigger resistance to RET inhibition in CCDC6-RET lung cancer cells, and endothelial cells may confer resistance to RET inhibitors by EGF. E7080 and other RET inhibitors may provide therapeutic benefits in the treatment of RET-positive lung cancer patients.
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.|Division of Hematology and Medical Oncology, Department of Internal Medicine, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Korea. hchang@ish.or.kr.
authors.forename: Hyun
authors.initials: H
authors.lastname: Chang
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Sung
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Sung Ung
authors.initials: SU
authors.lastname: Moon
authors.affiliation: Institute for Bio-Medical Convergence, Catholic Kwandong University College of Medicine, International St. Mary's Hospital, Incheon, Korea.
authors.forename: Han Soo
authors.initials: HS
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy / Q000235:genetics*; D045744:Cell Line, Tumor; D000068818:Cetuximab / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism; D000077156:Gefitinib; D015321:Gene Rearrangement; D017228:Hepatocyte Growth Factor / Q000494:pharmacology*; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D008175:Lung Neoplasms / Q000188:drug therapy / Q000235:genetics*; D020935:MAP Kinase Signaling System; D009154:Mutation; D009536:Niacinamide / Q000031:analogs & derivatives / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology; D010880:Piperidines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use; D000090063:Proto-Oncogene Mas; D051096:Proto-Oncogene Proteins c-ret / Q000037:antagonists & inhibitors* / Q000235:genetics; D011758:Pyrroles / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D000077157:Sorafenib; D000077210:Sunitinib; D051941:fms-Like Tyrosine Kinase 3 / Q000378:metabolism
chemical_list: C066855:HGF protein, human; D007211:Indoles; C000715470:MAS1 protein, human; D010671:Phenylurea Compounds; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011758:Pyrroles; D011799:Quinazolines; D034741:RNA, Small Interfering; D009536:Niacinamide; D004815:Epidermal Growth Factor; D017228:Hepatocyte Growth Factor; D000077157:Sorafenib; C512478:EGFR protein, human; D066246:ErbB Receptors; C497970:FLT3 protein, human; D051096:Proto-Oncogene Proteins c-ret; D051941:fms-Like Tyrosine Kinase 3; D000068818:Cetuximab; D000077156:Gefitinib; D000077210:Sunitinib; C452423:vandetanib
keywords: Lung cancer; RET oncogene; epidermal growth factor; resistance; tyrosine kinase inhibitor