According to Vogelstein, genetic mutations can produce a tyrosine kinase that is essentially "turned on" in the absence of a normal activation signal, which is called constitutive activation. This represents an ideal drug target, said Vogelstein, and is exemplified by the success of the drug Gleevec in treating chronic myeloid leukemia.
"In the past, the search for drug targets has been guided mechanistically by asking what karyotypic abnormalities are found in a cancer cell or what's responsible for a hereditary cancer predisposition," said Vogelstein. "But with the completion of the human genome sequence and the availability of the kinome, one can begin to think about how to do this in a much wider and unbiased sense."
The approach taken in this work actually represents a marriage of two technologies. "The availability of the human genome sequence allows scientists to scan sequences to identify kinases, and the increased speed with which DNA can be sequenced enables us to rapidly search for mutations in those kinases in human cancers," said Markowitz.
In beginning their survey of the kinome for kinases activated in colon cancers, the group first explored tyrosine kinases and related enzymes. To reduce the amount of gene sequencing required, they focused their search on mutations in the "kinase domain" of these enzymes, which is the region that is principally responsible for enzymatic activity.
"The kinase motifs are fairly stereotypical," said Markowitz. "They always include an adenosine triphosphate binding site and a set of conserved amino acid residues. That motif makes it possible to iden
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Contact: Jim Keeley
keeleyj@hhmi.org
301-215-8858
Howard Hughes Medical Institute
8-May-2003