EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation

Jingxuan Pan, Alfonso Quintás-Cardama, Hagop M. Kantarjian, Cem Akin, Taghi Manshouri, Peter Lamb, Jorge E. Cortes, Ayalew Tefferi, Francis J. Giles, Srdan Verstovsek

Research output: Contribution to journalArticle

Abstract

Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1) - HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

Original languageEnglish (US)
Pages (from-to)315-322
Number of pages8
JournalBlood
Volume109
Issue number1
DOIs
StatePublished - Jan 1 2007
Externally publishedYes

Fingerprint

Systemic Mastocytosis
Mast Cells
Protein-Tyrosine Kinases
Phosphorylation
Chemical activation
Cells
Apoptosis
Mutation
Tumors
STAT3 Transcription Factor
Gastrointestinal Stromal Tumors
Cell proliferation
Receptor Protein-Tyrosine Kinases
Cell Line
Bone
Phosphotransferases
Acute Myeloid Leukemia
In Vitro Techniques
Catalytic Domain
Bone Marrow

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

Cite this

Pan, J., Quintás-Cardama, A., Kantarjian, H. M., Akin, C., Manshouri, T., Lamb, P., ... Verstovsek, S. (2007). EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. Blood, 109(1), 315-322. https://doi.org/10.1182/blood-2006-04-013805

EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. / Pan, Jingxuan; Quintás-Cardama, Alfonso; Kantarjian, Hagop M.; Akin, Cem; Manshouri, Taghi; Lamb, Peter; Cortes, Jorge E.; Tefferi, Ayalew; Giles, Francis J.; Verstovsek, Srdan.

In: Blood, Vol. 109, No. 1, 01.01.2007, p. 315-322.

Research output: Contribution to journalArticle

Pan, J, Quintás-Cardama, A, Kantarjian, HM, Akin, C, Manshouri, T, Lamb, P, Cortes, JE, Tefferi, A, Giles, FJ & Verstovsek, S 2007, 'EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation', Blood, vol. 109, no. 1, pp. 315-322. https://doi.org/10.1182/blood-2006-04-013805
Pan, Jingxuan ; Quintás-Cardama, Alfonso ; Kantarjian, Hagop M. ; Akin, Cem ; Manshouri, Taghi ; Lamb, Peter ; Cortes, Jorge E. ; Tefferi, Ayalew ; Giles, Francis J. ; Verstovsek, Srdan. / EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation. In: Blood. 2007 ; Vol. 109, No. 1. pp. 315-322.
@article{3e744e018aa0413a969baaa81494a59f,
title = "EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation",
abstract = "Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1) - HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80{\%} of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.",
author = "Jingxuan Pan and Alfonso Quint{\'a}s-Cardama and Kantarjian, {Hagop M.} and Cem Akin and Taghi Manshouri and Peter Lamb and Cortes, {Jorge E.} and Ayalew Tefferi and Giles, {Francis J.} and Srdan Verstovsek",
year = "2007",
month = "1",
day = "1",
doi = "10.1182/blood-2006-04-013805",
language = "English (US)",
volume = "109",
pages = "315--322",
journal = "Blood",
issn = "0006-4971",
publisher = "American Society of Hematology",
number = "1",

}

TY - JOUR

T1 - EXEL-0862, a novel tyrosine kinase inhibitor, induces apoptosis in vitro and ex vivo in human mast cells expressing the KIT D816V mutation

AU - Pan, Jingxuan

AU - Quintás-Cardama, Alfonso

AU - Kantarjian, Hagop M.

AU - Akin, Cem

AU - Manshouri, Taghi

AU - Lamb, Peter

AU - Cortes, Jorge E.

AU - Tefferi, Ayalew

AU - Giles, Francis J.

AU - Verstovsek, Srdan

PY - 2007/1/1

Y1 - 2007/1/1

N2 - Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1) - HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

AB - Gain-of-function mutations of the receptor tyrosine kinase KIT play a key role in the pathogenesis of systemic mastocytosis (SM), gastrointestinal stromal tumors (GISTs), and some cases of acute myeloid leukemia (AML). Whereas KIT juxtamembrane domain mutations seen in most patients with GIST are highly sensitive to imatinib, the kinase activation loop mutant D816V, frequently encountered in SM, hampers the binding ability of imatinib. We investigated the inhibitory activity of the novel tyrosine kinase inhibitor EXEL-0862 against 2 subclones of human mast cell line-1 (HMC-1) - HMC-1.1, harboring the juxtamembrane domain mutation V560G, and HMC-1.2, carrying V560G and the activation loop mutation D816V, found in more than 80% of patients with SM. EXEL-0862 inhibited the phosphorylation of KIT in a dose-dependent manner and decreased cell proliferation in both mast cell lines with higher activity against HMC-1.2 cells. The phosphorylation of KIT-dependent signal transducer and activator of transcription-3 (STAT3) and STAT5 was abrogated upon exposure to nanomolar concentrations of EXEL-0862. In addition, EXEL-0862 induced a time- and dose-dependent proapoptotic effect in both mast cell lines and caused a significant reduction in mast-cell content in bone marrow samples from patients with SM harboring D816V and from those without the D816V mutation. We conclude that EXEL-0862 is active against KIT activation loop mutants and is a promising candidate for the treatment of patients with SM and other KIT-driven malignancies harboring active site mutations.

UR - http://www.scopus.com/inward/record.url?scp=33846019211&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=33846019211&partnerID=8YFLogxK

U2 - 10.1182/blood-2006-04-013805

DO - 10.1182/blood-2006-04-013805

M3 - Article

C2 - 16912224

AN - SCOPUS:33846019211

VL - 109

SP - 315

EP - 322

JO - Blood

JF - Blood

SN - 0006-4971

IS - 1

ER -