Researchers find East Asian TKI resistance gene

A team of researchers looking at a group of 5 leukemia patients have tagged a gene that could help to pick out those people who won't respond to tyrosine kinase inhibitors, the drugs once labeled as magic bullets.

Tyrosine kinase inhibitors, such as Novartis' ($NVS) Gleevec (imatinib), have made a huge difference in cancer, including chronic myeloid leukemia (CML) and some lung cancers. In fact, Gleevec made the cover of Time in 2001, lauded as the magic bullet that would treat cancer. Response rates are high and this group of drugs has been successful, but there are some patients who don't respond and who therefore undergo unnecessary treatment. The researchers, from Singapore and Japan, have found a common genetic mutation that seems to point to TKI resistance.

The team sequenced the genomes of 5 patients with CML, three who had shown resistance to TKIs. They found that all three of the resistant patients had the same mutation, in the BIM gene, which turned out to be a common variant, affecting around 1 in 8 East Asians, but few Africans and Europeans.

In CML patients, the mutation pinpointed those patients least likely to respond to TKIs. And in lung cancer patients, those with the mutation had shorter periods of response to drug treatment.

This gene mutation has potential as a biomarker in East Asian populations for selecting out the patients less likely to respond to this class of drugs, or who could have treatments personalized by using agents such as BH3 mimetics to "normalize" the response. In this time of increasing population mobility, the findings will also have significance for people in the West who have East Asian heritage.

"Asian CML patients could be screened for the presence of the deletion to determine the ones who have a higher chance of being resistant to TKI treatment," says Axel Hillmer at the A*STAR Genome Institute of Singapore. "It will be interesting to investigate the frequency of the deletion polymorphism in other populations and to translate the findings in the clinical practice."

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