Submitted February 15, 2007
Accepted August 5, 2007
Activity of TKI258 against primary cells and cell lines with FGFR1-fusion genes associated with the 8p11 myeloproliferative syndrome
Andrew Chase, Francis H. Grand, and Nicholas C.P. Cross*
Wessex Regional Genetics Laboratory, Salisbury and Human Genetics Division, University of Southampton, Salisbury, United Kingdom
* Corresponding author; email: ncpc{at}soton.ac.uk.
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 multi-targeted 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 IL-3 independence by ZNF198-FGFR1 or BCR-FGFR1 was specifically inhibited by TKI258 with IC50 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 to controls. This work provides evidence that targeted therapy may be beneficial for patients with EMS.
