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Proc Natl Acad Sci U S A. 2016 Aug 16;113(33):E4784-93. doi: 10.1073/pnas.1610179113. Epub 2016 Aug 1.

Distinct cellular properties of oncogenic KIT receptor tyrosine kinase mutants enable alternative courses of cancer cell inhibition.

Author information

1
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520;
2
Kolltan Pharmaceuticals Inc., New Haven, CT 06511.
3
Department of Pharmacology, Yale University School of Medicine, New Haven, CT 06520; irit.lax@yale.edu joseph.schlessinger@yale.edu.

Abstract

Large genomic sequencing analysis as part of precision medicine efforts revealed numerous activating mutations in receptor tyrosine kinases, including KIT. Unfortunately, a single approach is not effective for inhibiting cancer cells or treating cancers driven by all known oncogenic KIT mutants. Here, we show that each of the six major KIT oncogenic mutants exhibits different enzymatic, cellular, and dynamic properties and responds distinctly to different KIT inhibitors. One class of KIT mutants responded well to anti-KIT antibody treatment alone or in combination with a low dose of tyrosine kinase inhibitors (TKIs). A second class of KIT mutants, including a mutant resistant to imatinib treatment, responded well to a combination of TKI with anti-KIT antibodies or to anti-KIT toxin conjugates, respectively. We conclude that the preferred choice of precision medicine treatments for cancers driven by activated KIT and other RTKs may rely on clear understanding of the dynamic properties of oncogenic mutants.

KEYWORDS:

KIT; monoclonal antibody; oncogenic mutant; receptor tyrosine kinase; targeted therapy

PMID:
27482095
PMCID:
PMC4995958
DOI:
10.1073/pnas.1610179113
[Indexed for MEDLINE]
Free PMC Article

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