"We were able to sequence about 100 clinical samples, which gave us a very large body of data to shed light on the number of compound mutations and how they develop," said Michael Deininger, MD, PhD, co-senior author of the study, a professor of Internal Medicine, and an HCI investigator. "One key finding was that compound mutations containing an already known mutation called T315I tend to confer complete resistance to all available TKIs."
Working with HCI computational chemist Nadeem Vellore, PhD, the research team modeled at the molecular level why the drugs do not bind to certain BCR-ABL compound mutants. "This puts us in position to evaluate new drug candidates and work toward developing new treatments," said O'Hare.
"Computational analysis was one of the most interesting parts of the study. It not only confirmed what we found but showed the reason behind it," said Matthew Zabriskie, BS, co-lead author of the study. "We've established what the next level of TKI resistance is going to entail."
According to O'Hare, it is only a matter of time until analogous compound mutations emerge in many other cancers, including non-small cell lung cancer (NSCLC) and acute myeloid leukemia (AML). In these diseases, scientists and clinicians are still learning how to control single mutation-based resistance. "Our findings in CML will provide a blueprint for contending with resistance in these highly aggressive diseases as well," he said.
|Contact: Linda Aagard|
University of Utah Health Sciences