Tyrosine kinases (TKs) add phosphate moieties
to tyrosine residues on proteins that typically serve as docking sites to
recruit other molecules that bind and propagate signals. As such, they
function as central regulators of signaling pathways that control
transcription, cell cycle progression, differentiation, apoptosis and
other processes that are highly relevant to growth of cells and tissues.
Given this central position in regulation of growth, Bardelli et al raised
the question: why have mutations in TK genes been found in only a small
number of instances including certain human cancers? They speculated that
mutations do exist, but have yet to be detected because the vast number of
TK genes is only now becoming apparent as the human genome project
unfolds. To test this idea, they took advantage of high-throughput
sequencing and bioinformatics from the human genome project to search for
TK mutations in a select group of cancers, colorectal cancers.A recent
analysis organized the protein kinase complement of the human genome (the
"kinome") into a dendrogram containing nine broad groups or branches of
genes. Bardelli et al selected one major branch, which contained three
groups including 90 TK genes, 43 TK-like genes and 5 receptor guanylate
cyclase genes. Mutation analysis of 813 exons from the genomic database
carried out on DNA from 35 colorectal cancer cell lines yielded 14
mutations. Further analysis of DNA from 147 tumors identified 46 novel
mutations in 14 genes. All of the mutations were somatic in nature based
on comparison of DNA from tumor to matched normal tissues.
The authors suggested that mutations found in seven genes, which were
detected in more than one tumor, were functional rather than coincidental.
Based on the specific locations of the mutations, they further suggested
that many of the mutations were activating in nature, i.e., they resided
in key regions of the TK, such as the autoinhibitory activation loop. The
authors concluded that at least 30% of colorectal cancers contain at least
one mutation in the tyrosine kinome. They emphasized that an important
reason to study TK genes is that they provide attractive targets for
therapeutic intervention for growth disorders, noting the convincing
success of targeting BCR-ABL tyrosine kinase in leukemia (Druker BJ.
Cancer Cell 2002;1:31).
Bardelli A et al. Mutation Analysis of the Tyrosine Kinome in
Colorectal Cancers. Science 2003;300:949.
Editor’s Comment: While this paper specifically addresses cancer,
it does not take too much imagination to see its potential relevance to
growth of other tissues, such as the skeleton. Indeed, achondroplasia is
due to activating mutations of the FGFR3 tyrosine kinase. Given the scope
of regulation necessary to orchestrate and coordinate events in a growing
bone, it seems highly probable that there are other members, perhaps many,
of the tyrosine kinome involved. Accordingly, mutations of these as of yet
undefined TKs may underlie disorders of skeletal growth. Considering the
remarkable success of Gleevec in treating chronic myelogenous leukemia by
inhibiting the BCR-ABL TK, it is not inconceivable to dream of using
pharmacologic manipulation of growth-plate TKs to therapeutically manage
certain bone growth disturbances in the future.
William A. Horton, MD
