Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.

  title={Inhibition of constitutively active forms of mutant kit by multitargeted indolinone tyrosine kinase inhibitors.},
  author={Albert Tai-Ching Liao and May Chien and Narmada R. Shenoy and Dirk B. Mendel and Gerald Mcmahon and Julie M. Cherrington and Cheryl A. London},
  volume={100 2},
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 3 indolinones (SU11652, SU11654, and SU11655) that act as… 

Figures and Tables from this paper

Sensitivity toward tyrosine kinase inhibitors varies between different activating mutations of the FLT3 receptor.

Both deletion and insertion mutants led to factor-independent proliferation, indicating that both mutants have transforming capabilities, and it may be useful to determine the exact kind of FLT3 mutation when applying receptor kinase inhibitors in clinical trials.

In vitro and in vivo activity of ATP-based kinase inhibitors AP23464 and AP23848 against activation-loop mutants of Kit.

The sensitivities of both Kit mutant classes to the adenosine triphosphate (ATP)-based inhibitors AP23464 and AP23848 were determined to have therapeutic potential against D816V-expressing malignancies.

Sensitivity of oncogenic KIT mutants to the kinase inhibitors MLN518 and PD180970.

MLN518 is a promising candidate for the treatment of SM or AML with KIT mutations and 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.

Normal and Oncogenic Forms of the Receptor Tyrosine Kinase Kit

The objective of this review is to summarize what is known about normal and oncogenic forms of Kit and to place particular emphasis on recent developments in understanding the mechanisms of action of normal and activated forms of this RTK and its association with human disease.

Rapamycin inhibits growth and survival of D816V-mutated c-kit mast cells.

The data presented here provide a rationale to test whether rapamycin could be a possible treatment for SM and other hematologic malignancies with the D816V mutation, and show that both mutations constitutively activate the mammalian target ofRapamycin (mTOR) signaling pathway.

SU11652 Inhibits tyrosine kinase activity of FLT3 and growth of MV-4-11 cells

SU11652 is a potent FLT3 inhibitor which selectively targetsFLT3-ITD -positive MV-4-11 cells and should serve as a good candidate for development of therapeutic drugs to treat AML.

Gain-of-Function Mutations in the Extracellular Domain of KIT Are Common in Canine Mast Cell Tumors

This study shows that activating mutations in not only exon 11 but also exons 8 and 9 are common in canine mast cell tumors, and shows that Ba/F3 cells can be used for the direct characterization of canine KIT mutants, eliminating the need to make equivalent mutations in the mouse or human genes.

The novel HSP90 inhibitor STA-9090 exhibits activity against Kit-dependent and -independent malignant mast cell tumors.

Proof of target for SU11654: inhibition of KIT phosphorylation in canine mast cell tumors.

  • N. PryerLeslie B. Lee C. London
  • Biology, Medicine
    Clinical cancer research : an official journal of the American Association for Cancer Research
  • 2003
SU11654 treatment at the efficacious dose results in inhibition of KIT phosphorylation in canine MCTs and correlates target inhibition with mutational status of the c-kit juxtamembrane domain and SU11654 plasma concentration.

The stem cell factor receptor/c-Kit as a drug target in cancer.

The current knowledge on the signal transduction molecules and pathways activated by c-Kit under normal conditions and in cancer cells, and the role of aberrant c- Kit signaling in cancer progression are highlighted.



STI571 inactivation of the gastrointestinal stromal tumor c-KIT oncoprotein: biological and clinical implications

Cell-culture-based studies support an important role for c-KIT signaling in GIST and suggest therapeutic potential for STI571 in patients afflicted by this chemoresistant tumor.

Oncogenic mutation in the Kit receptor tyrosine kinase alters substrate specificity and induces degradation of the protein tyrosine phosphatase SHP-1.

This mutation activates the oncogenic potential of Kit by a novel mechanism involving an alteration in Kit substrate recognition and the degradation of SHP-1, an attenuator of the Kit signaling pathway.

Indolinone derivatives inhibit constitutively activated KIT mutants and kill neoplastic mast cells.

Indolinones show a direct correlation between inhibition of constitutively activated KIT and the death of neoplastic mast cells, and point to specific tyrosine kinase inhibitors as a potential therapy aimed directly at a cause of mastocytosis.

Neoplastic transformation of normal hematopoietic cells by constitutively activating mutations of c-kit receptor tyrosine kinase.

The results demonstrate a direct role of the mutant KITs, particularly KIT(V814), in tumorigenesis of hematopoietic cells and suggest that similar mutations may contribute to the development of human hematologic malignancies.

Ligand-independent activation of c-kit receptor tyrosine kinase in a murine mastocytoma cell line P-815 generated by a point mutation

Evidence is provided for a novel activating mutation of c-kit gene that might be involved in neoplastic growth or oncogenesis of some cell types, including mast cells.

Constitutive activation of c-kit in FMA3 murine mastocytoma cells caused by deletion of seven amino acids at the juxtamembrane domain.

The deletion of seven amino acids at the juxtamembrane domain appeared to be a new activating mutation of KIT that might be involved in neoplastic growth of mast cells.

The Kit-activating mutation D816V enhances stem cell factor--dependent chemotaxis.

Results demonstrate that the D816V Kit mutation enhances chemotaxis of CD117(+) cells, offering one explanation for increased mast cells observed in tissues of patients with mastocytosis.