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

Lierman, Els; Smits, Sanne; Cools, Jan; Dewaele, Barbara; Dębiec‐Rychter, Maria; Vandenberghe, Peter

doi:10.1038/leu.2012.8

Cited by 62 publications

(54 citation statements)

References 15 publications

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“…Ba/F3 cells expressing the other mutant, D842V, were found to be resistant against sunitinib, nilotinib and masitinib. Confirming previous observations (27), ponatinib was found to inhibit growth of Ba/F3 cells expressing the T674I mutant, and, less effectively, the growth of Ba/F3 cells expressing the D842V mutant ( Table 2). We were also able to confirm that ponatinib inhibits the phosphorylation of PDGFRA as well as phosphorylation of key downstream signaling molecules in Ba/F3 cells exhibiting wild type and mutant forms of FIP1L1-PDGFRA (Supplementary Figure S4).…”

Section: Effects Of Various Kinase Blockers On Growth Of Ba/f3 Cells supporting

confidence: 90%

“…Recently, several different TKI that can inhibit growth of FIP1L1-PDGFRA+ cells have been identified (12,14,15,(24)(25)(26)(27). Some of these agents were found to suppress the growth of Ba/F3 cells expressing various imatinib-resistant mutants of FIP1L1-PDGFRA.…”

Section: Discussionmentioning

confidence: 99%

“…Indeed, several novel TKI, such as nilotinib, dasatinib, sorafenib or PKC412 have been described to block the kinase-activity of FIP1L1-PDGFRA and thus malignant cell growth (12,14,15,(24)(25)(26). More recently, ponatinib was found to block the growth of Ba/F3 cells carrying various mutant-forms of FIP1L1-PDGFRA (27).…”

Section: Introductionmentioning

confidence: 99%

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Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA

Sadovnik

Lierman

Peter

et al. 2014

Experimental Hematology

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In chronic eosinophilic leukemia (CEL), the transforming oncoprotein FIP1L1-PDGFRA is a major target of therapy. In most patients, the tyrosine kinase inhibitor (TKI) imatinib induces complete remission. For patients who are intolerant or resistant, novel TKI have been proposed. We examined the in vitro effects of 14 kinase blockers on growth and function of EOL-1 cells, a FIP1L1-PDGFRA+ eosinophil cell line. Major growth-inhibitory effects were seen with all PDGFR-blocking agents, with IC 50 values in the low nM-range: ponatinib: 0.1-0.2 nM, sorafenib: 0.1-0.2 nM, masitinib: 0.2-0.5 nM, nilotinib: 0.2-1 nM, dasatinib: 0.5-2 nM, sunitinib: 1-2 nM, midostaurin: 5-10 nM. These drugs were also found to block activation of PDGFR-downstream signaling molecules, including Akt, S6, and STAT5 in EOL-1 cells. All effective TKI produced apoptosis in EOL-1 cells as determined by microscopy, Annexin-V/PI, and caspase-3-staining. In addition, PDGFR-targeting TKI were found to inhibit cytokine-induced migration of EOL-1 cells. In all bioassays employed, ponatinib was found to be the most potent compound in EOL-1 cells. In addition, ponatinib was found to downregulate expression of the activation-linked surface antigen CD63 on EOL-1 cells, and to suppress growth of primary neoplastic eosinophils. We also examined drug effects on Ba/F3 cells expressing two clinically relevant imatinib-resistant mutantforms of FIP1L1-PDGFRA, namely T674I and D842V. Strong inhibitory effects on both mutants were only seen with ponatinib. In summary, novel PDGFR-targeting TKI may be alternative

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Section: Effects Of Various Kinase Blockers On Growth Of Ba/f3 Cells supporting

confidence: 90%

Section: Discussionmentioning

confidence: 99%

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Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA

Sadovnik

Lierman

Peter

et al. 2014

Experimental Hematology

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“…Previous studies have shown in vitro activity of ponatinib against tyrosine kinases such as Bcr-Abl, FIP1L1-PDGFRa, KIT Y823D, and FGFR1 (22). Here, we validated the in vivo and in vitro activity of ponatinib against human mast cells to support further clinical evaluation of ponatinib in imatinib-resistant systemic mastocytosis patients.…”

Section: Discussionmentioning

confidence: 60%

“…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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Chronic myeloproliferative neoplasms

Vandenberghe¹,

Michaux²

2015

Cancer Cytogenetics

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

Cited by 62 publications

References 15 publications

Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA

Identification of Ponatinib as a potent inhibitor of growth, migration, and activation of neoplastic eosinophils carrying FIP1L1-PDGFRA

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

Chronic myeloproliferative neoplasms

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