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Identification of Ponatinib as a potent inhibitor of growth, migration, and
activation of neoplastic eosinophils carrying FIP1L1-PDGFRA
#MMPMID24407160
Sadovnik I
; Lierman E
; Peter B
; Herrmann H
; Suppan V
; Stefanzl G
; Haas O
; Lion T
; Pickl W
; Cools J
; Vandenberghe P
; Valent P
Exp Hematol
2014[Apr]; 42
(4
): 282-293.e4
PMID24407160
show ga
In chronic eosinophilic leukemia, 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 TKIs 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 IC50 values in the low nanomolar range: ponatinib,
0.1-0.2 nmol/L; sorafenib, 0.1-0.2 nmol/L; masitinib, 0.2-0.5 nmol/L; nilotinib,
0.2-1.0 nmol/L; dasatinib, 0.5-2.0 nmol/L; sunitinib, 1-2 nmol/L; midostaurin,
5-10 nmol/L. These drugs were also found to block activation of PDGFR-downstream
signaling molecules, including Akt, S6, and STAT5 in EOL-1 cells. All effective
TKIs produced apoptosis in EOL-1 cells as determined by microscopy, Annexin-V/PI,
and caspase-3 staining. In addition, PDGFR-targeting TKIs were found to inhibit
cytokine-induced migration of EOL-1 cells. In all bioassays used, 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 the growth of primary neoplastic eosinophils. We also
examined drug effects on Ba/F3 cells expressing two clinically relevant,
imatinib-resistant, mutant forms of FIP1L1-PDGFRA, namely T674I and D842V. Strong
inhibitory effects on both mutants were seen only with ponatinib. In summary,
novel PDGFR-targeting TKIs may be alternative agents for the treatment of
patients with imatinib-resistant chronic eosinophilic leukemia. Although several
different PDGFR-targeting agents are effective, the most potent drug appears to
be ponatinib.
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