Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome

Chase, Andrew, Bryant, Catherine, Score, Joannah and Cross, Nicholas C. P. (2013) Ponatinib as targeted therapy for FGFR1 fusions associated with the 8p11 myeloproliferative syndrome. Haematologica, 98 (1), 103-106. (doi:10.3324/haematol.2012.066407). (PMID:22875613)

Abstract

The 8p11 myeloproliferative syndrome is a rare, aggressive myeloproliferative neoplasm characterised by constitutively active FGFR1 fusion proteins that arise from specific
chromosomal translocations and which drive aberrant proliferation. Although FGFR1 inhibitors have shown in vitro activity against FGFR1 fusions, none are in use clinically and there is a need to assess additional compounds as potential therapy. Here we use cell lines
and primary cells to investigate ponatinib (AP24534). Ponatinib-treated Ba/F3 cells transformed by ZMYM2-FGFR1 and BCR-FGFR1 and the FGFR1OP2-FGFR1 positive
KG1A cell line showed reduced proliferation and decreased survival when compared to control cells. Inhibition induced apoptosis and reduced phosphorylation of the FGFR1 fusion
proteins and substrates. Ponatinib-treated cells from five 8p11 myeloproliferative syndrome patients showed reduced colony growth compared to controls. In one evaluable patient, ponatinib specifically reduced numbers of FGFR1-fusion gene positive colonies. Ponatinib therefore shows considerable promise for the treatment of patients with 8p11
myeloproliferative syndrome.

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Contributors

Author: Andrew Chase

Author: Nicholas C. P. Cross

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