In the studies published in Science, Sawyers and his colleagues demonstrated that BMS-354825 prolongs survival of mice with CML. In tests with cultured human bone marrow cells, the researchers showed that the drug inhibits the proliferation of bone marrow progenitor cells that are positive for BCR-ABL in patients who are resistant to Gleevec. "The bottom line is that our in vitro data indicate that this drug is active against all of the mutations except for one," Sawyers said.
At the time Sawyers and his colleagues were writing their Science article, there were 17 reported Gleevec-resistance mutations. There are more known now. Each mutation hampers Gleevec's ability to bind to its target, the ABL kinase.
Sawyers, who in addition to being a researcher, also sees cancer patients at UCLA, has long been hunting for an explanation of Gleevec resistance. Deftly moving between the clinic and the research lab, Sawyers has been at the center of understanding why Gleevec works for some patients, but stops working for others.
In September 2000, HHMI investigator John Kuriyan, a structural biologist then at The Rockefeller University, who had studied the regulation of Abl kinases for many years, made the seminal discovery that Gleevec, or STI-571, worked by binding to Abl when the enzyme was in its "off" position. If Abl was in the "on" position, the drug would not work.
In the arcane worlds of cellular signaling and structural biology, it was well known that Abl looks structurally quite similar to the Src family of oncogenes that also produce kinases. Yet, as Kuriyan's work demonstrated, STI-571 does not inhibit the Src proteins because they maintain a different shape when in their inactivated, or "off," position. As Kuriyan prophetically stated at the time, "The puzzle of STI-571's extreme aff
Contact: Jim Keeley
Howard Hughes Medical Institute