Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.
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 analyzed 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.
Oregon Health and Science University Cancer Institute, Portland, OR 97239, USA.
Amie S
AS
Corbin
Ian J
IJ
Griswold
Paul
P
La Rosée
Kevin W H
KW
Yee
Michael C
MC
Heinrich
Corinne L
CL
Reimer
Brian J
BJ
Druker
Michael W N
MW
Deininger
D000818:Animals; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D006801:Humans; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy / Q000235:genetics; D034721:Mastocytosis, Systemic / Q000188:drug therapy / Q000235:genetics; D051379:Mice; D020125:Mutation, Missense; D010879:Piperazines / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019009:Proto-Oncogene Proteins c-kit / Q000187:drug effects* / Q000235:genetics*; D011728:Pyridones / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D011799:Quinazolines / Q000494:pharmacology
D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011743:Pyrimidines; D011799:Quinazolines; C464670:tandutinib; D019009:Proto-Oncogene Proteins c-kit; C410732:PD 180970