title: The irreversible pan-HER inhibitor PF00299804 alone or combined with gemcitabine has an antitumor effect in biliary tract cancer cell lines.
abstract: Biliary tract cancer (BTC) is associated with poor survival and unresponsiveness to chemotherapy. Targeted therapies for BTC have been studied, and HER family members are promising therapeutic targets in BTC. In this study, we evaluated the efficacy of PF00299804, an irreversible pan-HER inhibitor, in eight BTC cell lines alone or combined with gemcitabine. PF00299804 potently inhibited the growth of two cell lines (SNU308 and SNU478) out of the eight BTC cell lines as a single agent. PF00299804 blocked HER family and downstream signaling pathways, inducing G1 arrest or apoptosis. Moreover, PF00299804 exerted synergistic effects with gemcitabine in seven of the eight BTC cell lines, possibly through the regulation of the genes involved in the response to gemcitabine, such as TS (thymidylate synthase), RRM1 (ribonucleotide reductase), and MAGEH1, which is negatively correlated with gemcitabine sensitivity. Our results support the need for further study of PF00299804 alone or combined with gemcitabine for the treatment of BTC.
authors.affiliation: Cancer Research Institute, Seoul National University College of Medicine, Seoul, South Korea.
authors.forename: Hyun-Jin
authors.initials: HJ
authors.lastname: Nam
authors.forename: Hwang-Phill
authors.initials: HP
authors.lastname: Kim
authors.forename: Young-Kwang
authors.initials: YK
authors.lastname: Yoon
authors.forename: Sang-Hyun
authors.initials: SH
authors.lastname: Song
authors.forename: Ah-Rum
authors.initials: AR
authors.lastname: Min
authors.forename: Sae-Won
authors.initials: SW
authors.lastname: Han
authors.forename: Seock-Ah
authors.initials: SA
authors.lastname: Im
authors.forename: Tae-You
authors.initials: TY
authors.lastname: Kim
authors.forename: Do-Youn
authors.initials: DY
authors.lastname: Oh
authors.forename: Yung-Jue
authors.initials: YJ
authors.lastname: Bang
mesh_terms: D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001661:Biliary Tract Neoplasms / Q000188:drug therapy; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003841:Deoxycytidine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004357:Drug Synergism; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D052999:Quinazolinones / Q000008:administration & dosage*; D017978:Receptors, Growth Factor / Q000037:antagonists & inhibitors*; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors; D000093542:Gemcitabine
chemical_list: D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D052999:Quinazolinones; D017978:Receptors, Growth Factor; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D003841:Deoxycytidine; C525726:dacomitinib; D051057:Proto-Oncogene Proteins c-akt; D000093542:Gemcitabine