title: Antitumor effect of the tyrosine kinase inhibitor nilotinib on gastrointestinal stromal tumor (GIST) and imatinib-resistant GIST cells.
abstract: Despite the benefits of imatinib for treating gastrointestinal stromal tumors (GIST), the prognosis for high risk GIST and imatinib-resistant (IR) GIST remains poor. The mechanisms of imatinib resistance have not yet been fully clarified. The aim of the study was to establish imatinib-resistant cell lines and investigate nilotinib, a second generation tyrosine kinase inhibitor (TKI), in preclinical models of GIST and imatinib-resistant GIST. For a model of imatinib-resistant GIST, we generated resistant cells from GK1C and GK3C cell lines by exposing them to imatinib for 6 months. The parent cell lines GK1C and GK3C showed imatinib sensitivity with IC50 of 4.59±0.97 µM and 11.15±1.48 µM, respectively. The imatinib-resistant cell lines GK1C-IR and GK3C-IR showed imatinib resistance with IC50 values of 11.74±0.17 µM (P<0.001) and 41.37±1.07 µM (P<0.001), respectively. The phosphorylation status of key cell signaling pathways, receptor tyrosine kinase KIT (CD117), platelet-derived growth factor receptor alpha (PDGFRA) and downstream signaling kinases: serine-threonine kinase Akt (AKT) and extracellular signal-regulated kinase 1/2 (ERK1/2) or the non-receptor tyrosine kinase: proto-oncogene tyrosine-protein kinase Src (SRC), was analyzed in established cell lines and ERK1/2 phosphorylation was found to be increased compared to the parental cells. Nilotinib demonstrated significant antitumor efficacy against GIST xenograft lines and imatinib-resistant GIST cell lines. Thus, nilotinib may have clinical potential for patients with GIST or imatinib-resistant GIST.
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Sako
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Fukuda
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yoshiro
authors.initials: Y
authors.lastname: Saikawa
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Rieko
authors.initials: R
authors.lastname: Nakamura
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tsunehiro
authors.initials: T
authors.lastname: Takahashi
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Norihito
authors.initials: N
authors.lastname: Wada
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hirohumi
authors.initials: H
authors.lastname: Kawakubo
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Hiroya
authors.initials: H
authors.lastname: Takeuchi
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Tai
authors.initials: T
authors.lastname: Ohmori
authors.affiliation: Department of Surgery, School of Medicine, Keio University, Shinjuku-ku, Tokyo, Japan.
authors.forename: Yuko
authors.initials: Y
authors.lastname: Kitagawa
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics; D006801:Humans; D000068877:Imatinib Mesylate / Q000008:administration & dosage; D051379:Mice; D009363:Neoplasm Proteins / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines / Q000008:administration & dosage*; D015398:Signal Transduction / Q000187:drug effects; D023041:Xenograft Model Antitumor Assays
chemical_list: C000715470:MAS1 protein, human; D009363:Neoplasm Proteins; D047428:Protein Kinase Inhibitors; D000090063:Proto-Oncogene Mas; D011743:Pyrimidines; D000068877:Imatinib Mesylate; C498826:nilotinib