The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations

Yongsheng Ma, Shan Zeng, Dean D. Metcalfe, Cem Akin, Sasa Dimitrijevic, Joseph H. Butterfield, Gerald McMahon, B. Jack Longley

Research output: Contribution to journalArticle

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Abstract

Mutations of c-KIT causing spontaneous activation of the KIT receptor kinase are associated with sporadic adult human mastocytosis (SAHM) and with human gastrointestinal stromal tumors. We have classified KIT-activating mutations as either "enzymatic site" type (EST) mutations, affecting the structure of the catalytic portion of the kinase, or as "regulatory" type (RT) mutations, affecting regulation of an otherwise normal catalytic site. Using COS cells expressing wild-type or mutant KIT, 2 compounds, STI571 and SU9529, inhibited wild-type and RT mutant KIT at 0.1 to 1 μM but did not significantly inhibit the Asp816Val EST mutant associated with SAHM, even at 10 μM. Using 2 subclones of the HMC1 mast cell line, which both express KIT with an identical RT mutation but which differ in that one also expresses the Asp816Val EST mutation, both compounds inhibited the RT mutant KIT, thereby suppressing proliferation and producing apoptosis in the RT mutant-only cell line. Neither compound suppressed activation of Asp816Val EST mutant KIT, and neither produced apoptosis or significantly suppressed proliferation of the cell line expressing the Asp816Val mutation. These studies suggest that currently available KIT inhibitors may be useful in treating neoplastic cells expressing KIT activated by its natural ligand or by RT activating mutations such as gastrointestinal stromal tumors but that neither compound is likely to be effective against SAHM. Furthermore, these results help establish a general paradigm whereby classification of mutations affecting oncogenic enzymes as RT or EST may be useful in predicting tumor sensitivity or resistance to inhibitory drugs.

Original languageEnglish (US)
Pages (from-to)1741-1744
Number of pages4
JournalBlood
Volume99
Issue number5
DOIs
StatePublished - Mar 1 2002

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Mastocytosis
Phosphotransferases
Cells
Mutation
Tumors
Chemical activation
Apoptosis
Gastrointestinal Stromal Tumors
Cell Line
Imatinib Mesylate
Ligands
COS Cells
Mast Cells
Enzymes
Pharmaceutical Preparations
Catalytic Domain

ASJC Scopus subject areas

  • Hematology

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The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. / Ma, Yongsheng; Zeng, Shan; Metcalfe, Dean D.; Akin, Cem; Dimitrijevic, Sasa; Butterfield, Joseph H.; McMahon, Gerald; Jack Longley, B.

In: Blood, Vol. 99, No. 5, 01.03.2002, p. 1741-1744.

Research output: Contribution to journalArticle

Ma, Yongsheng ; Zeng, Shan ; Metcalfe, Dean D. ; Akin, Cem ; Dimitrijevic, Sasa ; Butterfield, Joseph H. ; McMahon, Gerald ; Jack Longley, B. / The c-KIT mutation causing human mastocytosis is resistant to STI571 and other KIT kinase inhibitors; kinases with enzymatic site mutations show different inhibitor sensitivity profiles than wild-type kinases and those with regulatory-type mutations. In: Blood. 2002 ; Vol. 99, No. 5. pp. 1741-1744.
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