The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1

J. Pan, A. Quintás-Cardama, T. Manshouri, F. J. Giles, P. Lamb, A. Tefferi, J. Cortes, H. Kantarjian, S. Verstovsek

Research output: Contribution to journalArticle

Abstract

The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-α) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-α, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-α-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-α gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-α-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-α and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-α-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-α-positive HES.

Original languageEnglish (US)
Pages (from-to)1395-1404
Number of pages10
JournalLeukemia
Volume21
Issue number7
DOIs
StatePublished - Jul 2007
Externally publishedYes

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Hypereosinophilic Syndrome
Caspase 3
Protein-Tyrosine Kinases
Apoptosis
Platelet-Derived Growth Factor alpha Receptor
STAT3 Transcription Factor
Caspases
Phosphotransferases
Down-Regulation
Phosphorylation
Cell Line
Mutation
Genes
Imatinib Mesylate
Proteins

ASJC Scopus subject areas

  • Hematology
  • Oncology
  • Cancer Research

Cite this

Pan, J., Quintás-Cardama, A., Manshouri, T., Giles, F. J., Lamb, P., Tefferi, A., ... Verstovsek, S. (2007). The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1. Leukemia, 21(7), 1395-1404. https://doi.org/10.1038/sj.leu.2404714

The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1. / Pan, J.; Quintás-Cardama, A.; Manshouri, T.; Giles, F. J.; Lamb, P.; Tefferi, A.; Cortes, J.; Kantarjian, H.; Verstovsek, S.

In: Leukemia, Vol. 21, No. 7, 07.2007, p. 1395-1404.

Research output: Contribution to journalArticle

Pan, J, Quintás-Cardama, A, Manshouri, T, Giles, FJ, Lamb, P, Tefferi, A, Cortes, J, Kantarjian, H & Verstovsek, S 2007, 'The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1', Leukemia, vol. 21, no. 7, pp. 1395-1404. https://doi.org/10.1038/sj.leu.2404714
Pan, J. ; Quintás-Cardama, A. ; Manshouri, T. ; Giles, F. J. ; Lamb, P. ; Tefferi, A. ; Cortes, J. ; Kantarjian, H. ; Verstovsek, S. / The novel tyrosine kinase inhibitor EXEL-0862 induces apoptosis in human FIP1L1-PDGFR-α-expressing cells through caspase-3-mediated cleavage of Mcl-1. In: Leukemia. 2007 ; Vol. 21, No. 7. pp. 1395-1404.
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abstract = "The FIP1-like-1 (FIP1L1)-platelet-derived growth factor receptor-alpha (FIP1L1-PDGFR-α) fusion kinase causes hypereosinophilic syndrome (HES) in a defined subset of patients. Imatinib mesylate is a potent inhibitor of ABL but also of PDGFR-α, and has been associated with durable hematologic responses in patients with HES. However, development of mutations in the tyrosine kinase domain may hamper the activity of tyrosine kinase inhibitors (TKIs), which suggests that novel agents are warranted to prevent or overcome resistance. We evaluated the efficacy of the novel TKI EXEL-0862 in FIP1L1-PDGFR-α-expressing cell lines and in cells from a patient with HES harboring the FIP1L1-PDGFR-α gene. EXEL-0862 inhibited the proliferation of EOL-1 and imatinib-resistant T674I FIP1L1-PDGFR-α-expressing cells and resulted in potent inhibition of the phosphorylation of PDGFR-α and downstream proteins STAT3 and Erk1/2, both in vitro and ex vivo. Moreover, EXEL-0862 induced apoptotic death in EOL-1 cells and imatinib-resistant T674I FIP1L1-PDGFR-α-expressing cells, and resulted in significant downregulation of the antiapoptotic protein Mcl-1 through a caspase-dependent mechanism. Our data establish EXEL-0862 as a solid candidate for the targeted treatment of patients with FIP1L1-PDGFR-α-positive HES.",
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