Multidisciplinary Approach Identifies Antileukemia Drug Target

Cancer researchers have identified an enzyme that is active in acute myeloid leukemia (AML) cells, but that when silenced either genetically or chemically leads to differentiation of the cancer cells and attenuation of the leukemia.

Investigators at Harvard University (Cambridge, MA, USA) and the Massachusetts Institute of Technology (Cambridge, MA, USA) were aware that inhibitors of epidermal growth factor receptor (EGFR) induced acute myeloid leukemia (AML) differentiation despite the fact that AML cells did not express EGFR. In the current study, they integrated diverse chemical, proteomic, and genomic screening approaches to identify the actual target that was hit by the EGFR inhibitors.

Results published in the October 2009 issue of the journal Cancer Cell revealed that the real target was the enzyme spleen tyrosine kinase (Syk). Syk is expressed in blood cells where it is critical for proper blood cell differentiation. Recent studies have implicated Syk in blood cancers, specifically lymphomas and leukemias.

Pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. "With an orally available, well-tolerated Syk inhibitor currently in clinical development for other indications, our results should have immediate relevance for clinical testing of Syk inhibition in patients with AML," said senior author Dr. Kimberly Stegmaier, professor of pediatric oncology at Harvard University. "Our study also validates the feasibility of integrating genetic and proteomic approaches to identify small molecules and their mechanisms of action."

"Long term survival for patients with AML remains poor despite dose-intensive chemotherapy regimens," said Dr. Stegmaier. "For older adults, long-term survival is dismal, and many older patients are unable to tolerate standard cytotoxic therapy."

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