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 W.; Loriaux, Marc; Mohemmad, Qurish K.; Narasimhan, Narayana I.; Shakespeare, William C.; Wang, Frank; Druker, Brian J.; Clackson, Tim; Rivera, Victor M.

doi:10.1158/1535-7163.mct-10-1044

Cited by 130 publications

(97 citation statements)

References 26 publications

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“…Cell viability and growth were assessed using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega; ref. 39).…”

Section: Ba/f3 Tel-fgfr Cell Viability Assaymentioning

confidence: 99%

“…Cellular lysates (50 mg) were resolved by electrophoresis and membranes immunoblotted with antibodies against phospho and total proteins (39). IC 50 values were calculated by plotting percentage of phospho-protein normalized to total protein, or glyceraldehyde-3-phosphate dehydrogenase (GAPDH), of ponatinib-treated cells relative to vehicle-treated cells.…”

Section: Immunoblot Analysismentioning

confidence: 99%

“…Tumor xenografts were established by subcutaneous implantation of SNU16 ( (39). Tumor volume data were analyzed with a one-way ANOVA test (GraphPad Prism).…”

Section: Subcutaneous Xenograft Modelmentioning

confidence: 99%

“…Tumors were homogenized in Phospho-safe (Novagen) and immunoblotted as described above. Ponatinib concentrations in plasma were determined by an internal standard liquid chromatography/ tandem mass spectrometry method using protein precipitation and calibration standards prepared in blank mouse plasma (39). Table S1).…”

Section: Pharmacodynamic and Pharmacokinetic Analysesmentioning

confidence: 99%

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Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

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Members of the fibroblast growth factor receptor family of kinases (FGFR1-4) are dysregulated in multiple cancers. Ponatinib (AP24534) is an oral multitargeted tyrosine kinase inhibitor being explored in a pivotal phase II trial in patients with chronic myelogenous leukemia due to its potent activity against BCR-ABL. Ponatinib has also been shown to inhibit the in vitro kinase activity of all four FGFRs, prompting us to examine its potential as an FGFR inhibitor. In Ba/F3 cells engineered to express activated FGFR1-4, ponatinib potently inhibited FGFR-mediated signaling and viability with IC 50 values <40 nmol/L, with substantial selectivity over parental Ba/F3 cells. In a panel of 14 cell lines representing multiple tumor types (endometrial, bladder, gastric, breast, lung, and colon) and containing FGFRs dysregulated by a variety of mechanisms, ponatinib inhibited FGFR-mediated signaling with IC 50 values <40 nmol/L and inhibited cell growth with GI 50 (concentration needed to reduce the growth of treated cells to half that of untreated cells) values of 7 to 181 nmol/L. Daily oral dosing of ponatinib (10-30 mg/kg) to mice reduced tumor growth and inhibited signaling in all three tumor models examined. Importantly, the potency of ponatinib in these models is similar to that previously observed in BCR-ABL-driven models and plasma levels of ponatinib that exceed the IC 50 values for FGFR1-4 inhibition can be sustained in patients. These results show that ponatinib is a potent pan-FGFR inhibitor and provide strong rationale for its evaluation in patients with FGFR-driven cancers.

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“…Cell viability and growth were assessed using the CellTiter 96 Aqueous One Solution Cell Proliferation Assay (Promega; ref. 39).…”

Section: Ba/f3 Tel-fgfr Cell Viability Assaymentioning

confidence: 99%

Section: Immunoblot Analysismentioning

confidence: 99%

“…Tumor xenografts were established by subcutaneous implantation of SNU16 ( (39). Tumor volume data were analyzed with a one-way ANOVA test (GraphPad Prism).…”

Section: Subcutaneous Xenograft Modelmentioning

confidence: 99%

Section: Pharmacodynamic and Pharmacokinetic Analysesmentioning

confidence: 99%

See 2 more Smart Citations

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Gozgit¹,

Wong²,

Moran³

et al. 2012

Molecular Cancer Therapeutics

Self Cite

296

212

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show abstract

“…Besides, ponatinib also manifests inhibitory activity toward PDGFR, KIT, as well as FGFR (21,22). Although it has been reported that ponatinib is active against BaF3 cells stably expressing Y823D KIT in vitro (22) and D816V KIT-positive mast neoplastic cells (10), the in vivo effect remains to be examined.…”

Section: Introductionmentioning

confidence: 99%

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Jin

Ding

Pan

2014

Molecular Cancer Therapeutics

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Gain-of-function mutations of membrane receptor tyrosine kinase KIT, especially gatekeeper D816V point mutation in KIT, render kinase autoactivation, disease progression, and poor prognosis. D816V KIT is found in approximately 80% of the patients with systemic mastocytosis, and is resistant to the first and second generations of tyrosine kinase inhibitors (TKI). The purpose of this investigation was aimed at exploring whether ponatinib (AP24534), a novel effective TKI against T315I Bcr-Abl, was active against D816V KIT. We discovered that ponatinib abrogated the phosphorylation of KIT harboring either V560G (sensitive to imatinib) or D816V mutation (resistant to imatinib) and the downstream signaling transduction. Ponatinib inhibited the growth of D816V KIT-expressing cells in culture and nude mouse xenografted tumor. Ponatinib triggered apoptosis by inducing the release of cytochrome c and AIF, downregulation of Mcl-1. Furthermore, ponatinib abrogated the phosphorylation of b-catenin at the site Y654, suppressed the translocation of b-catenin, and inhibited the transcription and DNA binding of TCF and the expression of its targets (e.g., AXIN2, c-MYC, and CCND1). Moreover, ponatinib was highly active against xenografted D816V KIT tumors in nude mice and significantly prolonged the survival of mice with aggressive systemic mastocytosis or mast cell leukemia by impeding the expansion and infiltration of mast cells with imatinibresistant D814Y KIT. Our findings warrant a clinical trial of ponatinib in patients with systemic mastocytosis harboring D816V KIT. Mol Cancer Ther; 13(5); 1217-30. Ó2014 AACR.

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Functional characterization, localization, and inhibitor sensitivity of the TPR‐FGFR1 fusion in 8p11 myeloproliferative syndrome

Malli

Buxhofer‐Ausch

Rammer

et al. 2015

Genes Chromosomes & Cancer

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Myeloid and lymphoid neoplasms with fibroblast growth factor receptor 1 (FGFR1) abnormalities, also known as 8p11 myeloproliferative syndrome (EMS), represent rare and aggressive disorders, associated with chromosomal aberrations that lead to the fusion of FGFR1 to different partner genes. We report on a third patient with a fusion of the translocated promoter region (TPR) gene, a component of the nuclear pore complex, to FGFR1 due to a novel ins(1;8)(q25;p11p23). The fact that this fusion is a rare but recurrent event in EMS prompted us to examine the localization and transforming potential of the chimeric protein. TPR-FGFR1 localizes in the cytoplasm, although the nuclear pore localization signal of TPR is retained in the fusion protein. Furthermore, TPR-FGFR1 enables cytokine-independent survival, proliferation, and granulocytic differentiation of the interleukin-3 dependent myeloid progenitor cell line 32Dcl3, reflecting the chronic phase of EMS characterized by myeloid hyperplasia. 32Dcl3 cells transformed with the TPR-FGFR1 fusion and treated with increasing concentrations of the tyrosine kinase inhibitors ponatinib (AP24534) and infigratinib (NVP-BGJ398) displayed reduced survival and proliferation with IC50 values of 49.8 and 7.7 nM, respectively. Ponatinib, a multitargeted tyrosine kinase inhibitor, is already shown to be effective against several FGFR1-fusion kinases. Infigratinib, tested only against FGFR1OP2-FGFR1 to date, is also efficient against TPR-FGFR1. Taking its high specificity for FGFRs into account, infigratinib could be beneficial for EMS patients and should be further investigated for the treatment of myeloproliferative neoplasms with FGFR1 abnormalities.

show abstract

Potent Activity of Ponatinib (AP24534) in Models of FLT3-Driven Acute Myeloid Leukemia and Other Hematologic Malignancies

Cited by 130 publications

References 26 publications

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Ponatinib (AP24534), a Multitargeted Pan-FGFR Inhibitor with Activity in Multiple FGFR-Amplified or Mutated Cancer Models

Ponatinib Induces Apoptosis in Imatinib-Resistant Human Mast Cells by Dephosphorylating Mutant D816V KIT and Silencing β-Catenin Signaling

Functional characterization, localization, and inhibitor sensitivity of the TPR‐FGFR1 fusion in 8p11 myeloproliferative syndrome

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