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Prepublished online as a Blood First Edition Paper on April 17, 2002; DOI 10.1182/blood-2001-12-0350.
Submitted January 2, 2002
Accepted March 4, 2002
Inhibition of constitutively active forms of mutant kit by multi-targeted indolinone tyrosine kinase inhibitors
Cheryl A London*, Albert T Liao, May B Chien, Shenoy Narmada, Mendel B Dirk, McMahon Gerald, and Cherrington M Julie
Surgical and Radiological Sciences, UC Davis, School of Veterinary Medicine, Davis, CA, USA
SUGEN, Inc, South San Francisco, CA, USA
* Corresponding author; email: calondon{at}ucdavis.edu.
Mutations in the proto-oncogene c-kit, including point mutations, deletions, or duplications in the negative regulatory juxtamembrane (JM) domain or point mutations in the catalytic domain, have been observed in human and canine cancers and often result in constitutive activation of Kit in the absence of ligand binding. To identify a receptor tyrosine kinase (RTK) inhibitor capable of blocking the function of mutant Kit, we evaluated three indolinones (SU11652, SU11654 and SU11655) that act as competitive inhibitors of ATP binding to several members of the split kinase family of RTKs including VEGFR, FGFR, PDGFR and Kit. Mast cell lines expressing either WT Kit, a point mutation in the JM domain, a tandem duplication in the JM domain, and a point mutation in the catalytic domain were utilized for these studies. All three indolinones inhibited phosphorylation of WT Kit in the presence of SCF at concentrations as low as 0.01 µM. Autophosphorylation of both JM mutants was inhibited at 0.01-0.1 µM, resulting in cell cycle arrest within 24 hrs, while autophosphorylation of the catalytic domain mutant was inhibited at 0.25-0.5 µM, resulting in cell death within 24 hours. PARP cleavage was noted in all Kit mutant lines after indolinone treatment. In summary, SU11652, SU11654, and SU11655 are effective RTK inhibitors capable of disrupting the function of all forms of mutant Kit. As the concentrations of drug necessary for receptor inhibition are readily achievable and non-toxic in vivo, these compounds may have utility in the treatment of spontaneous cancers expressing Kit mutations.
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