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Moffitt researcher investigates 2-drug synergy to treat drug-resistant chronic myeloid leukemia
Date:10/25/2012

An interdisciplinary team of researchers has dissected a case of synergy in drug-resistant chronic myeloid leukemia to understand the mechanism by which two drugs, danusertib and bosutinib, work together to overcome resistance in the BCR-ABL gatekeeper mutation-specific disease. The team includes a researcher at Moffitt Cancer Center and colleagues at the CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences in Austria and the Massachusetts Institute of Technology. The goal is to address an unmet medical need because this BCR-ABL mutation confers resistance to all currently approved kinase inhibitors for chronic myeloid leukemia.

The study appeared in the Sept. 30 online version of Nature Chemical Biology.

"Treatment of chronic myeloid leukemia rapidly improved after the introduction of the first BCR-ABL inhibitor, Gleevec (imatinib)," said study co-author Uwe Rix, Ph.D., an assistant member of the Moffitt's Drug Discovery Department and Experimental Therapeutics Program. "However, it soon became apparent that a broad spectrum of possible resistance mechanisms necessitated second- and third-generation BCR-ABL inhibitors. Although these are mostly very successful, none of the currently approved options has been effective in patients with chronic myeloid leukemia who harbor the BCR-ABL gatekeeper mutation."

The researchers investigated the molecular mechanisms and logic underlying the synergistic interaction between danusertib and bosutinib, which is specific for BCR-ABL gatekeeper mutation-transformed cells. They applied a novel systems pharmacology approach involving a combination of different proteomics and gene expression profiling methods.

"We found previously unappreciated features of both agents," Rix said. "The synergy did not correlate with direct inhibition of BCR-ABL. Instead, our observations converged on the downstream MAPK signaling cascade as the predominantly affected pathway in
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Contact: Kim Polacek
kim.polacek@moffitt.org
813-745-7408
H. Lee Moffitt Cancer Center & Research Institute
Source:Eurekalert

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