Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome

The 8p11 myeloproliferative syndrome (EMS) is an aggressive, atypical stem cell myeloproliferative disorder associated with chromosome translocations that disrupt and constitutively activate FGFR1 by fusion to diverse partner genes. To explore the possibility of targeted therapy for EMS, we have investigated the use of TKI258, a multitargeted receptor tyrosine kinase inhibitor with activity against FGFR, VEGFR, PDGFR, FLT3, and KIT that is currently being assessed for the treatment of a variety of malignancies in phase 1 clinical studies. The viability of Ba/F3 cells transformed to IL3 independence by ZNF198-FGFR1 or BCR-FGFR1 was specifically inhibited by TKI258 with IC(50) values of 150 nM and 90 nM, respectively. Inhibition was accompanied by dose-dependent inhibition of phosphorylation of each fusion gene, ERK, and STAT5. TKI258 also specifically inhibited proliferation and survival of the FGFR1OP2-FGFR1-positive KG1 and KG1A cell lines, resulting in increased levels of apoptosis. Primary cells from EMS patients showed significant, dose-dependent responses in liquid culture and in methylcellulose colony assays compared with controls. This work provides evidence that targeted therapy may be beneficial for patients with EMS.

fibroblast growth factor, patients, laboratories, culture, phosphorylation, cell survival, human, genetics, type 1, cell line, protein, dna-binding proteins, inhibition, benzimidazoles, cell culture techniques, aged, humans, metabolism, tyrosine, proto-oncogene proteins c-bcr, cell proliferation, middle aged, quinolones, myeloproliferative disorders, oncogene proteins, pair 8, female, therapy, survival, male, syndrome, fusion, treatment, tumor, evaluation studies, transcription factors, apoptosis, pathology, pharmacology, receptor, activity, drug effects, growth, proto-oncogene proteins, proteins, chromosomes, research, adult, genes, protein kinase inhibitors, research support

10.1182/blood-2007-02-074286

0006-4971

3729-3734

Chase, A.F.H.

a40a09c2-3073-4655-ba0b-a802e34914b5

Cross, N.C.

6b31788a-9b23-4938-ace2-5610032377a3

2007

Chase, A.F.H.

a40a09c2-3073-4655-ba0b-a802e34914b5

Cross, N.C.

6b31788a-9b23-4938-ace2-5610032377a3

Chase, A.F.H. and Cross, N.C. (2007) Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome. Blood, 110 (10), 3729-3734. (doi:10.1182/blood-2007-02-074286).

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Published date: 2007

Keywords: fibroblast growth factor, patients, laboratories, culture, phosphorylation, cell survival, human, genetics, type 1, cell line, protein, dna-binding proteins, inhibition, benzimidazoles, cell culture techniques, aged, humans, metabolism, tyrosine, proto-oncogene proteins c-bcr, cell proliferation, middle aged, quinolones, myeloproliferative disorders, oncogene proteins, pair 8, female, therapy, survival, male, syndrome, fusion, treatment, tumor, evaluation studies, transcription factors, apoptosis, pathology, pharmacology, receptor, activity, drug effects, growth, proto-oncogene proteins, proteins, chromosomes, research, adult, genes, protein kinase inhibitors, research support

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