Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies

Joseph M. Gozgit, Matthew J. Wong, Scott Wardwell, Jeffrey Tyner, Marc Loriaux, Qurish K. Mohemmad, Narayana I. Narasimhan, William C. Shakespeare, Frank Wang, Brian Druker, Tim Clackson, Victor M. Rivera

Research output: Contribution to journalArticle

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Abstract

Ponatinib (AP24534) is a novel multitargeted kinase inhibitor that potently inhibits native and mutant BCRABL at clinically achievable drug levels. Ponatinib also has in vitro inhibitory activity against a discrete set of kinases implicated in the pathogenesis of other hematologic malignancies, including FLT3, KIT, fibroblast growth factor receptor 1 (FGFR1), and platelet derived growth factor receptor α (PDGFRα). Here, using leukemic cell lines containing activated forms of each of these receptors, we show that ponatinib potently inhibits receptor phosphorylation and cellular proliferation with IC50 values comparable to those required for inhibition of BCR-ABL (0.3 to 20 nmol/L). The activity of ponatinib against the FLT3-ITD mutant, found in up to 30% of acute myeloid leukemia (AML) patients, was particularly notable. In MV4-11 (FLT3-ITD+/+) but not RS4;11 (FLT3-ITD-/-) AML cells, ponatinib inhibited FLT3 signaling and induced apoptosis at concentrations of less than 10 nmol/L. In an MV4-11 mouse xenograft model, once daily oral dosing of ponatinib led to a dose-dependent inhibition of signaling and tumor regression. Ponatinib inhibited viability of primary leukemic blasts from a FLT3-ITD positive AML patient (IC50 4 nmol/L) but not those isolated from 3 patients with AML expressing native FLT3. Overall, these results support the investigation of ponatinib in patients with FLT3-ITD - driven AML and other hematologic malignancies driven by KIT, FGFR1, or PDGFRα.

Original languageEnglish (US)
Pages (from-to)1028-1035
Number of pages8
JournalMolecular Cancer Therapeutics
Volume10
Issue number6
DOIs
StatePublished - Jun 2011

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Hematologic Neoplasms
Acute Myeloid Leukemia
Receptor, Fibroblast Growth Factor, Type 1
Platelet-Derived Growth Factor Receptors
Inhibitory Concentration 50
Phosphotransferases
ponatinib
Myeloid Cells
Heterografts
Phosphorylation
Cell Proliferation
Apoptosis
Cell Line

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. / Gozgit, Joseph M.; Wong, Matthew J.; Wardwell, Scott; Tyner, Jeffrey; Loriaux, Marc; Mohemmad, Qurish K.; Narasimhan, Narayana I.; Shakespeare, William C.; Wang, Frank; Druker, Brian; Clackson, Tim; Rivera, Victor M.

In: Molecular Cancer Therapeutics, Vol. 10, No. 6, 06.2011, p. 1028-1035.

Research output: Contribution to journalArticle

Gozgit, JM, Wong, MJ, Wardwell, S, Tyner, J, Loriaux, M, Mohemmad, QK, Narasimhan, NI, Shakespeare, WC, Wang, F, Druker, B, Clackson, T & Rivera, VM 2011, 'Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies', Molecular Cancer Therapeutics, vol. 10, no. 6, pp. 1028-1035. https://doi.org/10.1158/1535-7163.MCT-10-1044
Gozgit, Joseph M. ; Wong, Matthew J. ; Wardwell, Scott ; Tyner, Jeffrey ; Loriaux, Marc ; Mohemmad, Qurish K. ; Narasimhan, Narayana I. ; Shakespeare, William C. ; Wang, Frank ; Druker, Brian ; Clackson, Tim ; Rivera, Victor M. / Potent activity of ponatinib (AP24534) in models of FLT3-driven acute myeloid leukemia and other hematologic malignancies. In: Molecular Cancer Therapeutics. 2011 ; Vol. 10, No. 6. pp. 1028-1035.
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AU - Loriaux, Marc

AU - Mohemmad, Qurish K.

AU - Narasimhan, Narayana I.

AU - Shakespeare, William C.

AU - Wang, Frank

AU - Druker, Brian

AU - Clackson, Tim

AU - Rivera, Victor M.

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