Distorted. A mutation (red) in the kinase Bcr-Abl enzyme overcomes a new cancer drug.
The anti-leukemia drug known as Gleevec or STI-571 was announced as the vanguard of a new generation of drugs against cancer of the designer. Unfortunately, some advanced leukemias become resistant to treatment. Now, a new study shows that this resistance can be caused by either mutation or gene amplification makes the target of the drug.
Most drugs against cancer were discovered by screening thousands of random chemicals to see if cancer cells kill. But STI-571 was designed specifically to inhibit certain kinases enzymes, including those produced by the Bcr-Abl oncogene that fuels the growth of cancer cells in chronic myeloid leukemia (CML). Almost all patients treated in the early stages of CML respond to the drug, and some have been in remission for over 2 years. However, the drug was less effective in patients with advanced disease. These people sometimes go into remission on medication - which almost never happens with older treatments -. But 80% relapse within one year
To understand the mechanism of this resistance, Charles Sawyers of the University of California, Los Angeles, and colleagues first analyzed the activity level Bcr-Abl kinase in tumor cells of 11 patients who had relapsed. They detected high levels in all cells - an unexpected finding, because these cells are genetically unstable and could have thwarted the drug by another change. In six patients, the reason turned out to be a point mutation that alters the Bcr-Abl enzyme, allowing him to avoid drugs, while maintaining the kinase activity which stimulates the growth of tumor cells. In three others, additional copies of the gene overwhelmed the drug by producing more enzyme he could handle.
The fact that changes in the target enzyme responsible for drug resistance is encouraging, said Brian Druker of Oregon Health Sciences University in Portland, because it means targeting the kinase Bcr Abl or protein interacts with another promising strategy for the fight against cancer. Future treatment options include the design of additional kinase inhibitors that are given with STI-571, because the enzyme should be less able to become resistant to all drugs at once.
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