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Ref Type Journal Article
PMID (17698633)
Authors Chase A, Grand FH, Cross NC
Title Activity of TKI258 against primary cells and cell lines with FGFR1 fusion genes associated with the 8p11 myeloproliferative syndrome.
Journal Blood
Vol 110
Issue 10
Date 2007 Nov 15
URL
Abstract Text 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.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
FGFR1 fusion acute myeloid leukemia sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) increased apoptosis and inhibited survival of acute myelogenous leukemia cell lines harboring FGFR1OP2-FGFR1 fusion in culture (PMID: 17698633). 17698633
FGFR1 fusion Advanced Solid Tumor sensitive Dovitinib Preclinical Actionable In a preclinical study, Dovitinib (TKI258) inhibited Erk, Stat5 signaling and survival of transformed cell lines overexpressing FGFR1 fusion proteins (ZMYM2-FGFR1 or BCR-FGFR1) in culture (PMID: 17698633). 17698633
FGFR1 rearrange myeloproliferative neoplasm sensitive Dovitinib Preclinical Actionable In a preclinical study, primary cells from 8p11 myeloproliferative syndrome patients harboring FGFR1 rearrangement were sensitive to Dovitinib (TKI258)-induced growth inhibition in culture (PMID: 17698633). 17698633