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Jun 25, 2001
 |  BioCentury  |  Tools & Techniques

The upside of Gleevec resistance

Rather than see bad news, researchers can find positive take away messages in last week's publication of findings showing the mechanisms of resistance to Novartis AG's recently approved Gleevec imatinib for chronic myeloid leukemia.

First, the paper in Science showed the continued viability of the target pathway, led by the aberrant kinase Bcr-Abl, even among drug resistant patients. Second, it suggested that kinase-dependent cancers could be managed using combination therapies. And more generally, the work illustrated the speed at which the ability to elucidate mechanisms of action, track mutations and achieve other molecular insights might enable research to move forward.

The paper, by researchers at the University of California at Los Angeles, shows that among patients in the advanced phases of CML who relapse while taking Gleevec, some developed a mutation in the pocket on Bcr-Abl where Gleevec binds to disrupt its activity, while others experienced an amplification of Bcr-Abl that disappears after they stop treatment with Gleevec (see B17).

The mutation was the same in all patients who had it: a single amino acid substitution of isoleucine for threonine. Although they noted that the mutated Bcr-Abl form could have been present in patients before Gleevec treatment started, the researchers said they could not find evidence of it in pre-treatment samples from the patients, suggesting that it developed after treatment began.

"Therefore, the primary explanation for disease progression in these patients appears to be Bcr-Abl dependent proliferation rather than secondary oncogenic signals that permit Bcr-Abl independent growth," the authors wrote.

Thus, "the work continues to validate the target," Charles Sawyers, professor of medicine at UCLA's Jonsson Cancer Center and an author on the paper, told BioCentury. "The cancer cell could have chosen an opposite strategy, but instead it mutates...

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