title: Antitumor activity of HM781-36B, a pan-HER tyrosine kinase inhibitor, in HER2-amplified breast cancer cells.
abstract: HM781-36B is an orally administered pan-human epidermal growth factor receptor (HER) inhibitor. To explore the role of pan-HER inhibitor in breast cancer, we investigated the antitumor effect and mechanisms of HM781-36B in breast cancer cell lines. Six breast cancer cell lines (BT474, MDA-MB-453, SK-BR-3, T47D, MCF-7, and MDA-MB-231) were tested. The growth inhibitory effect was assessed using the tetrazolium bromide [3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl-tetrazolium bromide] assay. The cell cycle at various concentrations of HM781-36B was analyzed by flow cytometry, and analysis of downstream molecules was performed by western blot analysis. Interaction of HM781-36B with cytotoxic chemotherapeutic agents was analyzed by combination index using CalcuSyn. The HER2-amplified cells (SK-BR-3, BT474, and MDA-MB-453) were sensitive to HM781-36B (IC50=0.001 μmol/l, 0.0012 μmol/l, and 0.0095 μmol/l, respectively). HM781-36B induced G1 arrest and resulted in apoptosis. It reduced the level of p-HER2, p-AKT, p-ERK, and p-STAT3. HM781-36B combined with 5-fluorouracil, cisplatin, paclitaxel, or gemcitabine showed a synergistic inhibitory effect on the HER2-amplified and on some of the HER2-nonamplified breast cancer cells. HM781-36B could be a promising treatment for HER2-amplified breast cancer as a single agent or in combination with cytotoxic agents and can be a candidate for treatment of HER2-nonamplified breast cancer in combination with cytotoxic agents.
authors: Cancer Research Institute, Seoul, Korea.
authors: Hye Jin
authors: HJ
authors: Kim
authors: Hwang-Phill
authors: HP
authors: Kim
authors: Young-Kwang
authors: YK
authors: Yoon
authors: Maeng-Sup
authors: MS
authors: Kim
authors: Gwan-Sun
authors: GS
authors: Lee
authors: Sae-Won
authors: SW
authors: Han
authors: Seock-Ah
authors: SA
authors: Im
authors: Tae-You
authors: TY
authors: Kim
authors: Do-Youn
authors: DY
authors: Oh
authors: Yung-Jue
authors: YJ
authors: Bang
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D002945:Cisplatin / Q000008:administration & dosage; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004305:Dose-Response Relationship, Drug; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D017239:Paclitaxel / Q000008:administration & dosage; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology*; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D050796:STAT3 Transcription Factor / Q000378:metabolism; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D002945:Cisplatin; D003841:Deoxycytidine; D005472:Fluorouracil; D017239:Paclitaxel; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D050796:STAT3 Transcription Factor; D000093542:Gemcitabine; C557213:HM781-36B; C494086:STAT3 protein, human; C508053:ERBB2 protein, human