Activity of fibroblast growth factor receptor inhibitors TKI258, ponatinib and AZD4547 against TPR-FGFR1 fusion

Abstract

8p11 myeloproliferative syndrome (EMS) is a rare disease characterized by the constitutive activation of fibroblast growth factor receptor 1 (FGFR1). To date, four cases of EMS with the chromosomal translocation, t(1;8)(q25;p11.2), have been reported. In the present study, TPR-FGFR1-expressing Baf3 cells were established and confirmed by polymerase chain reaction. To identify the most promising drug for EMS, the activities and associated mechanism of three tyrosine kinase inhibitors (TKIs), TKI258, ponatinib and AZD4547, against TPR-FGFR1 were tested by MTT assay, flow cytometry and western blot. The data demonstrated that TPR-FGFR1 was localized in the cytoplasm, and was able to transform interleukin-3-dependent hematopoietic Baf3 cells into growth factor-independent cells. All of the three TKIs markedly inhibited the proliferation of TPR-FGFR1-expressing Baf3 cells, and the activation of FGFR1 and the downstream signaling molecules, extracellular signal-regulated kinase 1/2, phospholipiase Cγ and signal transducer and activator of transcription 5. AZD4547 was the most efficient drug, and TKI258 was the least. By contrast, no significant difference was found among the three drugs on their effect on cell apoptosis. Taken together, the data obtained in the present study suggested that AZD4547 had increased potency, compared with TKI258 and ponatinib, for the treatment of EMS.

The 8p11 myeloproliferative syndrome: Genotypic and phenotypic classification and targeted therapy

“…CFU-GM was not inhibited by dovitinib, but BFU-Es were strongly inhibited at all below 100nM ( 117 ). In addition, the in vitro data of dovitinib compared with other TKIs are not ideal, and larger doses are required to achieve the same degree of inhibitory effect as other TKIs ( 118 ). The difference in efficacy between dovitinib and other TKIs may be related to the non-selective expression level of this kinase and the inhibition of the number of other potential kinases and downstream biological efficacy.…”

“…Dasatinib is an oral small molecule inhibitor that inhibits nonmutated BCR-ABL and most known BCR-ABL mutants; its targeting includes PDGFR, cKIT, SFK (SRC family kinase), FGFR1, and EGFR ( 114 ). Several clinical examples suggest that dasatinib is more suitable for EMS patients with cardiovascular disease than ponatinib, and the patients benefited for more than 9 months and significantly improved the patient’s quality of life ( 118 , 119 ). Perhaps dasatinib might be more suitable for the treatment of elderly and frail EMS patients with cardiovascular disease, and it improves the PB, prolongs the survival time of patients, and provides another treatment option in addition to hematopoietic stem cell transplantation.…”