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Mechanisms of ibrutinib resistance identified in chronic lymphocytic leukemia
Date:5/29/2014

COLUMBUS, Ohio A new study has discovered how resistance develops in patients taking ibrutinib, a new and highly effective drug for the treatment of chronic lymphocytic leukemia (CLL).

The study was published in the New England Journal of Medicine and led by researchers at The Ohio State University Comprehensive Cancer Center Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC James). It identifies gene mutations that cause ibrutinib resistance in CLL patients.

"Knowledge of these mutations is the first step in the development of drugs or drug combinations that might prevent or treat ibrutinib-resistant CLL," says co-principal investigator John C. Byrd, MD, director, division of hematology, and professor of medicine, of medicinal chemistry and of veterinary biosciences at Ohio State.

"Importantly, we saw none of these mutations in patients before they used ibrutinib," says Amy Johnson, PhD, associate professor of medicine in the division of hematology, an OSUCCC James researcher and a co-principal investigator of the study.

Ibrutinib (Imbruvica) works by permanently binding with a protein called Bruton's tyrosine kinase (BTK), a molecule that CLL cells need to grow and proliferate. BTK is one in a chain of proteins that relays growth signals from the surface of CLL cells to genes in the cell nucleus. By blocking BTK, ibrutinib halts the flow of these growth signals, and the CLL cells die (see illustration below).

The researchers found, however, that CLL cells can develop a mutation in BTK itself that weakens the ability of ibrutinib to bind with the protein. This leaves the drug less able to block BTK's action. The researchers also found two mutations in a protein that comes after BTK in the signaling pathway. Those mutations allow growth signals to travel the pathway even when BTK is blocked, rendering ibrutinib ineffective.

An estimated 15,700 new cases of C
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Contact: Amanda Harper
amanda.harper2@osumc.edu
614-685-5420
Ohio State University Wexner Medical Center
Source:Eurekalert

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