One of the truly spectacular success stories in modern oncology is the development and implementation of Gleevec, a drug that virtually halts the progress of chronic myeloid leukemia. Yet for some patients who harbor particularly stubborn genetic mutations, Gleevec fails miserably.
Now, Howard Hughes Medical Institute (HHMI) researchers at the University of California, Los Angeles, and colleagues at Bristol-Myers Squibb Oncology in Princeton, NJ, are reporting the first description of a new compound that is designed to overcome Gleevec resistance in some of these individuals.
In an article published in the July 16, 2004, issue of the journal Science, HHMI investigator Charles L. Sawyers, Neil P. Shah and colleagues at UCLA's Jonsson Comprehensive Cancer Center, report that the compound BMS-354825, which is under development by Bristol-Myers Squibb, successfully sidesteps the vexing problem of Gleevec (imatinib) resistance.
“The identification of this compound as a drug candidate is a direct byproduct of understanding why patients develop resistance to Gleevec,” said Sawyers. He notes that just as Gleevec was developed as a “molecularly targeted” inhibitor, the next generations of Gleevec, of which is BMS-354825 is one, will be refined and improved by structural biology studies that show how the drugs “fit” with their target, and how mutations alter the shape of that target.
The all-important drug target in chronic myeloid leukemia (CML) is an enzyme called Abelson tyrosine kinase (ABL), which becomes overactivated by a chromosomal mix-up that occurs during blood cell development. The genes ABL and BCR, which are located on different chromosomes, become fused and express a hybrid BCR-ABL enzyme that is always active. The hyperactive BCR-ABL, in turn, drives the overproliferation of white blood cells that is the hallmark of CML.
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 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 are turned on and off is a matter of extreme interest.”