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Molecular Targets for Therapy

Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities

Leukemia volume 27, pages 32–40 (2013)Cite this article

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Abstract

Myeloid and lymphoid malignancies associated with fibroblast growth factor receptor-1 (FGFR1) abnormalities are characterized by constitutively activated FGFR1 kinase and rapid transformation to acute myeloid leukemia and lymphoblastic lymphoma. Molecular targeted therapies have not been widely used for stem cell leukemia/lymphoma (SCLL). Ponatinib (AP24534), which potently inhibits native and mutant BCR-ABL, also targets the FGFR family. Using murine BaF3 cells, stably transformed with six different FGFR1 fusion genes, as well as human KG1 cells expressing activated chimeric FGFR1 and five newly established murine SCLL cell lines, we show that ponatinib (<50 nM) can effectively inhibit phosphoactivation of the fusion kinases and their downstream effectors, such as PLCγ, Stat5 and Src. Ponatinib also significantly extended survival of mice transplanted with different SCLL cell lines. Ponatinib administered at 30 mg/kg daily also significantly delayed, or even prevented, tumorigenesis of KG1 cells in xenotransplanted mice. Furthermore, we demonstrate that ponatinib specifically inhibits cell growth and clonogenicity of normal human CD34+ progenitor cells transformed by chimeric FGFR1 fusion kinases. Overall, our data provide convincing evidence to suggest that pharmacologic inhibition of FGFR1 fusion kinases with ponatinib is likely to be beneficial for patients with SCLL and perhaps for other human disorders associated with dysregulated FGFR1 activity.

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Acknowledgements

We are grateful to Dr Els Lierman for providing the CUX1-FGFR1 vector. Ponatinib was kindly provided by Ariad Pharmaceuticals Inc. This work was supported by Grant CA076167 from the National Institutes of Health.

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  1. Georgia Health Sciences University, Cancer Center, Augusta, GA, USA

    M Ren, H Qin, R Ren & J K Cowell

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Correspondence to M Ren or J K Cowell.

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Ren, M., Qin, H., Ren, R. et al. Ponatinib suppresses the development of myeloid and lymphoid malignancies associated with FGFR1 abnormalities. Leukemia 27, 32–40 (2013). https://doi.org/10.1038/leu.2012.188

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