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Study Provides Blueprint for Next Generation of Chronic Myeloid Leukemia Treatment

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Key Points

  • BCR-ABL compound mutations can lead to clinical failure of tyrosine kinase inhibitors that are otherwise effective against single mutations.
  • T315I-inclusive compound mutations confer complete resistance to all available tyrosine kinase inhibitors, including ponatinib.

Researchers at Huntsman Cancer Institute (HCI) at the University of Utah have identified and characterized mutated forms of the gene that encodes BCR-ABL, the unregulated enzyme driving chronic myeloid leukemia (CML). The findings by Zabriskie et al were published in Cancer Cell.

Although tyrosine kinase inhibitors targeting BCR-ABL (such as ponatinib [Iclusig], imatinib [Gleevec], and nilotinib [Tasigna]) do not cure CML, they are effective at controlling the disease in a way that allows patients to return to normal life. Before the advent of tyrosine kinase inhibitors, the 5-year survival rate for CML was 30% at best; now that number is above 95%. However, 20% to 30% of patients with CML become resistant to one or more of these agents.

Most cases of CML resistance result from a single mutation in BCR-ABL, and drugs to control resistance to tyrosine kinase inhibitor treatment caused by various single mutations have already been discovered. However, BCR-ABL compound mutants that contain two mutations in the same molecule can lead to clinical failure of these tyrosine kinase inhibitors.

Study Details

The research team focused on BCR-ABL compound mutants observed in patients and tested them against all approved tyrosine kinase inhibitors, creating a dataset that can potentially help clinicians decide which drug will be most effective for each mutation combination. They found that none of the tyrosine kinase inhibitors are effective for some compound mutations, indicating the need for further research to accommodate the growing population of CML patients.

“Fortunately, the problems we are studying affect a minority of CML patients, but still this leaves some patients with no good treatment option at all,” said Thomas O’Hare, PhD, an HCI investigator and co–senior author of the study. He is also Research Associate Professor of Internal Medicine, Division of Hematology and Hematologic Malignancies. “Our goal is to have a tyrosine kinase inhibitor option for every patient.”

“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, 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 tyrosine kinase inhibitors.”

Structural Model for Compound Mutations

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 Dr. 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 tyrosine kinase inhibitor resistance is going to entail.”

According to Dr. O’Hare, it is only a matter of time until analogous compound mutations emerge in many other cancers, including non–small cell lung cancer and acute myeloid leukemia. 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.

Dr. O’Hare is the corresponding author for the Cancer Cell article

The study was supported by the Leukemia & Lymphoma Society, the American Society of Hematology, Howard Hughes Medical Institute, Huntsman Cancer Foundation, and grants from the National Institutes of Health/National Cancer Institute.

The content in this post has not been reviewed by the American Society of Clinical Oncology, Inc. (ASCO®) and does not necessarily reflect the ideas and opinions of ASCO®.


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