Ranking the kinase kingdom
After four years of work, researchers at the Wellcome Trust Sanger Institute and colleagues have elucidated the prevalence and signature of somatic mutations in human protein kinases. The findings, recently reported in Nature, have provided surprising insights into the number of kinases that may be legitimate targets for cancer treatment, and challenged conventional thinking about which kinases should be priorities for drug developers.
The paper has already led some companies to change their research strategies.
Given that kinases represent the protein family most commonly found among known cancer genes, and the recent success of kinase inhibitors as cancer treatments, the authors hypothesized that a genome-wide search for kinase mutations in tumors would result in the discovery of new targets.
The researchers sequenced the 518 known kinase genes in 210 cancer tissue samples (including breast, lung, colorectal, gastric, testis, ovarian, renal, melanoma, glioma and acute lymphoblastic leukemia) to characterize potentially cancer-associated mutations. They then ranked the kinases according to the likelihood that the mutations they contained could have a causal role in disease, calling these "driver mutations."
The researchers also examined 537 non-redundant pathways containing different combinations of kinases and produced a list of pathways ranked by their probability of having at least one driver mutation.
Some kinases that ranked high on the list were surprises and will need further studies to elucidate whether they are actually involved in cancer. For example, the number one potential culprit was Titin (TTN), a kinase that is involved in muscle contraction and has never before been implicated in cancer.
Many other kinases on the list