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Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases

Leukemia volume 26, pages 1693–1695 (2012)Cite this article

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Imatinib, the small molecule inhibitor of BCR-ABL1, has revolutionized treatment of chronic myeloid leukemia (CML), and of other malignancies driven by deregulation of imatinib-sensitive tyrosine kinases, for example PDGFRA, PDGFRB or KIT. Yet, selection of imatinib-resistant kinase domain mutations is curtailing CML response rates. Ponatinib is a third-generation kinase inhibitor with potent activity towards wild-type BCR-ABL1, as well as numerous imatinib-resistant BCR-ABL1 kinase domain mutants, including the notorious T315I mutation.1

Patients with myeloid neoplasms with eosinophilia, and the FIP1L1-PDGFRA fusion gene, are exquisitely sensitive to imatinib and many of them reach a durable molecular remission under imatinib.2, 3 Yet, rare cases of secondary resistance have also been reported, with the acquisition of a T674I mutation in seven patients and a D842V mutation in one (for a recent overview, see Metzgeroth et al.4).3, 4, 5 The FIP1L1-PDGFRA-T674I mutation has limited to absent sensitivity to nilotinib and dasatinib in vitro but responds well to sorafenib.6, 7 However, the effect of sorafenib in two patients with the FIP1L1-PDGFRA-T674I mutation was limited and variable: no response was obtained in one case, whereas in the other patient, a short-lived response was followed by selection of the panresistant FIP1L1-PDGFRA-D842V mutation and blast crisis.4, 7 Myeloid/lymphoid neoplasms associated with eosinophilia and a rearrangement of FGFR1, also known as the 8p11 myeloproliferative syndrome (EMS), are aggressive stem cell disorders.8 Although, the FGFR1 fusion kinase constitutes a potential therapeutic target, the disease remains medically untreatable today. Finally, various KIT mutations are pathogenic drivers in gastrointestinal stromal tumors (GIST), systemic mastocytosis (SM) and other malignancies. The KIT-D816V mutation occurs in SM and melanoma and is primarily resistant to imatinib. In GIST, KIT-W557_K558del mutations are common and respond well to imatinib treatment, but here also different secondary mutations (T670I and D820A) are known that confer resistance.9 Besides its activity against BCR-ABL1, the activity of ponatinib in vitro also encompasses PDGFRA, KIT and FGFR1.1 Potent activity towards oncogenic fusion or mutant kinases such as FIP1L1-PDGFRA, KIT-N822K and FGFR1OP2-FGFR1 has also been documented.10 Therefore, we investigated the effect of ponatinib on imatinib-resistant mutations of FIP1L1-PDGFRA, of KIT and on an imatinib-insensitive FGFR1 fusion.

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Acknowledgements

This work was supported by grants from KU Leuven (GOA/11/010 to JC, PV) and FWO-Vlaanderen (G.0509.10 to PV) and the Interuniversity Attraction Poles (IAP) granted by the Federal Office for Scientific, Technical and Cultural Affairs, Belgium (JC and PV). EL is a postdoctoral fellow from FWO-Vlaanderen. PV is a senior clinical investigator from FWO-Vlaanderen.

Author contributions

EL designed the study, performed research, analyzed the data and wrote the paper; SS performed research and analyzed the data; BDW and MDB provided the KIT constructs and analyzed the KIT data; JC provided the FIPL1-PDGFRA mutants and revised the article for intellectual content; PV designed the study, analyzed the data and wrote the paper.

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Authors and Affiliations

  1. Center for Human Genetics, KU Leuven, Leuven, Belgium

    E Lierman, S Smits, J Cools, M Debiec-Rychter & P Vandenberghe

  2. Department of Molecular and Developmental Genetics, CME - VIB11, Leuven, Belgium

    J Cools

  3. Center for Human Genetics, University Hospital Leuven, Leuven, Belgium

    E Lierman, B Dewaele, M Debiec-Rychter & P Vandenberghe

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  1. E Lierman
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Correspondence to P Vandenberghe.

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Lierman, E., Smits, S., Cools, J. et al. Ponatinib is active against imatinib-resistant mutants of FIP1L1-PDGFRA and KIT, and against FGFR1-derived fusion kinases. Leukemia 26, 1693–1695 (2012). https://doi.org/10.1038/leu.2012.8

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