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Genetic Factors May Drive Imatinib Resistance

Kate Traynor

Researchers have discovered two ways that the gene responsible for chronic myeloid leukemia (CML) can adapt to avoid the inhibitory effects of Novartis’ imatinib mesylate product, Gleevec.

CML is common among people who have the Philadelphia chromosome, a genetic defect that encodes the aberrant BCR-ABL protein. This protein helps direct the explosive replication of white blood cells that characterizes CML. Imatinib mesylate acts by blocking an adenosine triphosphate (ATP) binding site on the BCR-ABL protein and thus stopping the biochemical cascade that results in CML.

Six of 11 patients whose advanced CML relapsed after an initial response to treatment with imatinib mesylate were found to have an identical mutation in the ABL coding region. The mutation led to a single substitution of isoleucine for threonine in the ABL protein and apparently prevented imatinib—but not ATP—from occupying the ATP-binding site. A molecularly cloned version of the mutated gene also encoded a protein that was resistant to inactivation by imatinib mesylate in vitro.

Three of the 11 patients, including one who also had the ABL mutation, bore an additional Philadelphia chromosome that contained multiple copies of the BCR-ABL gene. Presumably, these patients produced greater quantities of BCR-ABL protein than imatinib could handle at the dosage given. Amplification of the gene continued throughout imatinib therapy. In one patient, the Philadelphia chromosome duplicate was present before drug treatment began, but the additional BCR-ABL genes were undetectable four weeks after imatinib mesylate therapy ceased.

These findings appeared in the June 21 Sciencexpress, the online version of the journal Science.

Imitinib mesylate was approved by the Food and Drug Administration May 10, less than three months after Novartis submitted a new drug application for the product. Novartis, in a press release issued a week after the Sciencexpress article was published, emphasized that, so far, resistance to imatinib has been observed only in patients with advanced CML.

Novartis said that "maturing Phase II data" from ongoing clinical trials document the product’s effectiveness. Survival among patients with CML in the chronic phase—an early form of the disease—is about 98 percent after one year, Novartis reported. Half of all patients with advanced CML have survived for seven months after starting imatinib mesylate therapy, which Novartis said exceeds the median prognosis, three to six months, observed with conventional chemotherapy.

Novartis also reported that the company is conducting clinical trials of imatinib mesylate in combination with other drugs as well as against other types of cancer.