title: Antitumor Activity of HM781-36B, alone or in Combination with Chemotherapeutic Agents, in Colorectal Cancer Cells.
abstract: OBJECTIVE
  HM781-36B is a novel and irreversible pan-human epidermal growth factor receptor (HER) inhibitor with TEC cytoplasmic kinase inhibition. The aim of this study is to evaluate the antitumor activity and mechanism of action for HM781-36B in CRC cell lines.
  
  
  METHODS
  The CRC cell lines were exposed to HM781-36B and/or oxaliplatin (L-OHP), 5-fluorouracil (5-FU), SN-38. The cell viability was examined by Cell Titer-Glo luminescent cell viability assay kit. Change in the cell cycle and protein expression was determined by flow cytometry and immunoblot analysis, respectively. Synergism between 2 drugs was evaluated by the combination index.
  
  
  RESULTS
  The addition of HM781-36B induced potent growth inhibition in both DiFi cells with EGFR overexpression and SNU-175 cells (IC50, 0.003 µM and 0.005 µM, respectively). Furthermore, HM781-36B induced G1 arrest of the cell cycle and apoptosis, and reduced the levels of HER family and downstream signaling molecules, pERK and pAKT, as well as nonreceptor/cytoplasmic tyrosine kinase, BMX. The combination of HM781-36B with 5-FU, L-OHP, or SN-38 showed an additive or synergistic effect in most CRC cells.
  
  
  CONCLUSIONS
  These findings suggest the potential roles of HM781-36B as the treatment for EGFR-overexpressing colon cancer, singly or in combination with chemotherapeutic agents. The role of BMX expression as a marker of response to HM781-36B should be further explored.
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea ; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Mi Hyun
authors.initials: MH
authors.lastname: Kang
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea ; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Sung Ung
authors.initials: SU
authors.lastname: Moon
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea ; Biomedical Research Institute, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Ji Hea
authors.initials: JH
authors.lastname: Sung
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jin Won
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Keun Wook
authors.initials: KW
authors.lastname: Lee
authors.affiliation: Department of Pathology, Seoul National University Bundang Hospital, Seongnam, Korea.
authors.forename: Hye Seung
authors.initials: HS
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jong Seok
authors.initials: JS
authors.lastname: Lee
authors.affiliation: Division of Hematology and Medical Oncology, Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, Seongnam, Korea.
authors.forename: Jee Hyun
authors.initials: JH
authors.lastname: Kim
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D002166:Camptothecin / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D015179:Colorectal Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D005472:Fluorouracil / Q000494:pharmacology / Q000627:therapeutic use; D059585:G1 Phase Cell Cycle Checkpoints / Q000187:drug effects; D006801:Humans; D000077146:Irinotecan; D009944:Organoplatinum Compounds / Q000494:pharmacology / Q000627:therapeutic use; D000077150:Oxaliplatin; D014176:Protein Biosynthesis / Q000187:drug effects; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology* / Q000627:therapeutic use*
chemical_list: D000970:Antineoplastic Agents; C557213:HM781-36B; D009944:Organoplatinum Compounds; D011799:Quinazolines; D000077150:Oxaliplatin; D000077146:Irinotecan; C492367:BMX protein, human; C089848:Tec protein-tyrosine kinase; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D051057:Proto-Oncogene Proteins c-akt; D048049:Extracellular Signal-Regulated MAP Kinases; D005472:Fluorouracil; D002166:Camptothecin
keywords: BMX; Colorectal neoplasm; Epidermal growth factor receptor-neu receptor; HM781-36B