期刊
CANCER CELL
卷 16, 期 4, 页码 281-294出版社
CELL PRESS
DOI: 10.1016/j.ccr.2009.08.018
关键词
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资金
- National Cancer Institute [5K08 CA098444]
- Howard Hughes Medical Institute
- Sidney Kimmel Cancer Foundation
- Claudia Adams Barr Foundation
- Gloria Spivak Support Fund
Cell-based screening can facilitate the rapid identification of compounds inducing complex cellular phenotypes. Advancing a compound toward the clinic, however, generally requires the identification of precise mechanisms of action. We previously found that epidermal growth factor receptor (EGFR) inhibitors induce acute myeloid leukemia (AML) differentiation via a non-EGFR mechanism. In this report, we integrated proteomic and RNAi-based strategies to identify their off-target, anti-AML mechanism. These orthogonal approaches identified Syk as a target in AML. Genetic and pharmacological inactivation of Syk with a drug in clinical trial for other indications promoted differentiation of AML cells and attenuated leukemia growth in vivo. These results demonstrate the power of integrating diverse chemical, proteomic, and genomic screening approaches to identify therapeutic strategies for cancer.
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