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Cancer Cell DOI:10.1016/j.ccr.2009.08.018

Proteomic and genetic approaches identify Syk as an AML target.

Publication TypeJournal Article
Year of Publication2009
AuthorsHahn, CK, Berchuck, JE, Ross, KN, Kakoza, RM, Clauser, K, Schinzel, AC, Ross, L, Galinsky, I, Davis, TN, Silver, SJ, Root, DE, Stone, RM, DeAngelo, DJ, Carroll, M, Hahn, WC, Carr, SA, Golub, TR, Kung, AL, Stegmaier, K
JournalCancer Cell
Date Published2009 Oct 06
KeywordsAnimals, Antineoplastic Agents, Cell Differentiation, Cell Proliferation, Cell Survival, Dose-Response Relationship, Drug, Gene Expression Profiling, Gene Expression Regulation, Leukemic, Genomics, HL-60 Cells, Humans, Inhibitory Concentration 50, Intracellular Signaling Peptides and Proteins, Leukemia, Myeloid, Acute, Male, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, SCID, Oxazines, Phosphorylation, Protein Kinase Inhibitors, Protein-Tyrosine Kinases, Proteomics, Pyridines, Quinazolines, RNA Interference, Syk Kinase, Tandem Mass Spectrometry, Time Factors, Tumor Cells, Cultured, Tyrosine, U937 Cells, Xenograft Model Antitumor Assays

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.


Alternate JournalCancer Cell
PubMed ID19800574
PubMed Central IDPMC2803063
Grant ListK08 CA098444 / CA / NCI NIH HHS / United States
K08 CA098444-05 / CA / NCI NIH HHS / United States
5K08 CA098444 / CA / NCI NIH HHS / United States
/ / Howard Hughes Medical Institute / United States