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. In the case of both Gleevec and BMS-354825, there appears to be one particular mutation, known as T315I, which does not respond to either therapy. "That mutation will likely require a different drug, and researchers are working on that now," said Sawyers.
Sawyers, who in addition to being a researcher, also sees cancer patients at UCLA, has long been hunting for an explanation of Gleevec resistance. The development of BMS-354825 is deeply rooted in scientific literature spanning several different fields, including molecular oncology and structural biology. 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 affinity and specificity is of broader interest because protein kinases are crucial elements in signal transduction pathways that control cell growth, cell death and other processes. Thus, understanding how kinases
Contact: Jim Keeley
Howard Hughes Medical Institute