CAMBRIDGE, MA Researchers have devised a way to identify genetic mutations that will cause resistance to targeted anti-cancer drugs, even before patients are treated a finding that will aid scientists involved in drug development and allow physicians to monitor patients for resistance problems before they occur.

Scientists at Whitehead Institute for Biomedical Research developed the screen to identify mutations that cause patients with chronic myeloid leukemia, or CML, to become resistant to Gleevec, a "magic bullet" cancer-fighting drug that targets the protein produced by BCR/ABL, the gene that causes this rare form of leukemia.

"In the leukemia cells of a CML patient, BCR/ABL is constantly mutating," said George Daley, leader of the research team that developed the screening strategy. "Cells carrying certain mutations can resist the drug and continue to grow while the remainder of leukemia cells are suppressed. We have found a way to discover those mutations experimentally."

In studies reported March 21 in the journal Cell, the scientists used recombinant DNA methods to randomly mutate the BCR/ABL gene to mimic potential variations that might be found in CML patients. The mutated genes were then transferred into millions of mouse blood cells and exposed to Gleevec. While most cells succumbed to the drug, some of the cells with specific variations thrived.

"We looked for those cells that continued to grow, extracted them and sequenced their genes," said Mohammad Azam, a postdoctoral researcher at Whitehead and lead author of this new study, which was supported by the National Institutes of Health. That examination revealed 15 mutations researchers elsewhere had previously linked to Gleevec resistance in CML patients plus 97 more. As research on the mutations continues and more patients are surveyed, more of these mutations are likely to be found.

With the catalogue of mutations in hand, Daley said, physicians could one
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Contact: Kelli Whitlock
whitlock@wi.mit.edu
617-258-9183
Whitehead Institute for Biomedical Research
20-Mar-2003

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