title: Preclinical evaluation of nilotinib efficacy in an imatinib-resistant KIT-driven tumor model.
abstract: The novel KIT inhibitor nilotinib is currently being evaluated for its clinical utility in the treatment of gastrointestinal stromal tumor. However, the effects of nilotinib in cells expressing commonly occurring KIT mutations remain to be fully defined. The aim of this study was therefore to investigate the efficacy of nilotinib against cells expressing imatinib-sensitive or imatinib-resistant KIT mutations and to evaluate [(18)F] fluorodeoxyglucose-positron emission tomography (FDG-PET) imaging as a biomarker of nilotinib response in vivo. Nilotinib inhibited the proliferation of imatinib-responsive V560G-KIT FDC-P1 and imatinib-resistant D816V-KIT FDC-P1 cells with a GI(50) of 4.9 and 630 nmol/L, respectively, whereas apoptosis studies revealed that nilotinib and imatinib were equipotent against the V560G cell line. In contrast, although 10 micromol/L nilotinib induced >50% apoptosis in the D816V cells at 16 hours, 10 micromol/L imatinib had no effect on cell survival at 24 hours. Syngeneic DBA2/J mice bearing FDC-P1-KIT tumors were evaluated for response to nilotinib by FDG-PET. V560G-KIT FDC-P1 tumor FDG uptake was significantly reduced compared with baseline levels following 2 days of nilotinib treatment. In contrast, no effect of nilotinib was observed on tumor growth or FDG-PET uptake into D816V tumors despite intratumoral drug levels reaching in excess of 10 micromol/L at 4 hours after dosing. Biomarker analysis revealed the inhibition of KIT phosphorylation in V560G but not D816V tumors. These findings show the in vivo activity of nilotinib in the treatment of tumors bearing V560G-KIT but not D816V-KIT and the utility of FDG-PET imaging to assess tumor response to this agent.
authors.affiliation: Translational Research Laboratory, Research Division, East Melbourne, Victoria, Australia.
authors.forename: Carleen
authors.initials: C
authors.lastname: Cullinane
authors.forename: Anthony
authors.initials: A
authors.lastname: Natoli
authors.forename: Yorlon
authors.initials: Y
authors.lastname: Hui
authors.forename: Nelly
authors.initials: N
authors.lastname: Conus
authors.forename: Susan
authors.initials: S
authors.lastname: Jackson
authors.forename: Joseph
authors.initials: J
authors.lastname: Brüggen
authors.forename: Paul W
authors.initials: PW
authors.lastname: Manley
authors.forename: Grant A
authors.initials: GA
authors.lastname: McArthur
mesh_terms: D019943:Amino Acid Substitution / Q000235:genetics / Q000502:physiology; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D001549:Benzamides; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D019008:Drug Resistance, Neoplasm / Q000187:drug effects / Q000235:genetics*; D006801:Humans; D000068877:Imatinib Mesylate; D051379:Mice; D008811:Mice, Inbred DBA; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics* / Q000502:physiology; D011743:Pyrimidines / Q000494:pharmacology / Q000627:therapeutic use*; D014185:Transplantation, Isogeneic; D016896:Treatment Outcome
chemical_list: D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; C498826:nilotinib