Proteomic and Genetic Approaches Identify Syk as an AML Target

作者：Hahn Cynthia K; Berchuck Jacob E; Ross Kenneth N; Kakoza Rose M; Clauser Karl; Schinzel Anna C; Ross Linda; Galinsky Ilene; Davis Tina N; Silver Serena J; Root David E; Stone Richard M; DeAngelo Daniel J; Carroll Martin; Hahn William C; Carr Steven A; Golub Todd R; Kung Andrew L; Stegmaier Kimberly^*

来源：Cancer Cell, 2009, 16(4): 281-294.

DOI：10.1016/j.ccr.2009.08.018

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.

• 出版日期2009-10-6