title: ETV6-NTRK3 as a therapeutic target of small molecule inhibitor PKC412.
abstract: The ETV6-NTRK3 (EN) fusion gene which encodes a chimeric tyrosine kinase was first identified by cloning of the t(12;15)(p13;q25) translocation in congenital fibrosarcoma (CFS). Since then, EN has been also found in congenital mesoblastic nephroma (CMN), secretory breast carcinoma (SBC) and acute myelogenous leukemia (AML). Using IMS-M2 and M0-91 cell lines harboring the EN fusion gene, and Ba/F3 cells stably transfected with EN, we demonstrated that PKC412, also known as midostaurin, is an inhibitor of EN. Inhibition of EN activity by PKC412 suppressed the activity of it downstream molecules leading to inhibition of cell proliferation and induction of apoptosis. Our data for the first time suggested that PKC412 could serve as therapeutic drug for treatment of patients with this fusion.
authors.affiliation: Department of Medical Genome Sciences, Graduate School of Frontier Sciences, The University of Tokyo, Tokyo 108-8639, Japan. kk086406@mgs.k.u-tokyo.ac.jp
authors.forename: Hoang Thanh
authors.initials: HT
authors.lastname: Chi
authors.forename: Bui Thi Kim
authors.initials: BT
authors.lastname: Ly
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Kano
authors.forename: Arinobu
authors.initials: A
authors.lastname: Tojo
authors.forename: Toshiki
authors.initials: T
authors.lastname: Watanabe
authors.forename: Yuko
authors.initials: Y
authors.lastname: Sato
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D020929:Mitogen-Activated Protein Kinase Kinases / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology; D015514:Oncogene Proteins, Fusion / Q000037:antagonists & inhibitors*; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D050799:STAT5 Transcription Factor / Q000378:metabolism; D019311:Staurosporine / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein
chemical_list: D000970:Antineoplastic Agents; D020929:Mitogen-Activated Protein Kinase Kinases; D015514:Oncogene Proteins, Fusion; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D050799:STAT5 Transcription Factor; D019311:Staurosporine; C484319:ETV6-NTRK3 fusion protein, human; D020812:Receptor, trkC; D000097764:ETS Translocation Variant 6 Protein; C059539:midostaurin