TY - JOUR
T1 - Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970
AU - Corbin, Amie S.
AU - Griswold, Ian J.
AU - La Rosée, Paul
AU - Yee, Kevin W.H.
AU - Heinrich, Michael C.
AU - Reimer, Corinne L.
AU - Druker, Brian J.
AU - Deininger, Michael W.N.
PY - 2004/12/1
Y1 - 2004/12/1
N2 - Oncogenic mutations of the receptor tyrosine kinase KIT occur In gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analysed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.
AB - Oncogenic mutations of the receptor tyrosine kinase KIT occur In gastrointestinal stromal tumors (GISTs), some cases of acute myelogenous leukemia (AML), and systemic mastocytosis (SM). GISTs commonly contain mutations of the KIT juxtamembrane region while SM and AML harbor active site KIT mutations. Imatinib, which potently inhibits juxtamembrane mutants, is effective for the treatment of GISTs but has no activity against active site mutants. We analysed the inhibitory potential of 2 small molecule inhibitors, MLN518 and PD180970, against different classes of KIT mutants. Both compounds inhibit the growth of cell lines expressing juxtamembrane mutant KIT. MLN518 additionally targets active site mutant cell lines, inhibiting cell proliferation, KIT, and signal transducer and activator of transcription-3 (Stat3) phosphorylation and inducing apoptosis at concentrations that may be clinically achievable. As phase 1 clinical trials of MLN518 in AML have shown little toxicity, our data suggest MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations.
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U2 - 10.1182/blood-2004-06-2189
DO - 10.1182/blood-2004-06-2189
M3 - Article
C2 - 15304388
AN - SCOPUS:9444258068
SN - 0006-4971
VL - 104
SP - 3754
EP - 3757
JO - Blood
JF - Blood
IS - 12
ER -