Research article summary (published 4 Oct 2009):

Proteomic and genetic approaches identify Syk as an AML target.

Full Abstract

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.

Author information

Author/s: Hahn, Cynthia K (CK); Berchuck, Jacob E (JE); Ross, Kenneth N (KN); Kakoza, Rose M (RM); Clauser, Karl (K); Schinzel, Anna C (AC); Ross, Linda (L); Galinsky, Ilene (I); Davis, Tina N (TN); Silver, Serena J (SJ); Root, David E (DE); Stone, Richard M (RM); DeAngelo, Daniel J (DJ); Carroll, Martin (M); Hahn, William C (WC); Carr, Steven A (SA); Golub, Todd R (TR); Kung, Andrew L (AL); Stegmaier, Kimberly (K);

Affiliation: Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.

Grants: 5K08 CA098444 (Agency:NCI NIH HHS) ; (Agency:Howard Hughes Medical Institute)

Journal and publication information

Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't

Journal: Cancer cell (Cancer Cell), published in United States. (Language: eng)

Reference: 2009-Oct; vol 16 (issue 4) : pp 281-94

Dates: Created 2009/10/05; Completed 2009/10/15;

PMID: 19800574, status: MEDLINE (last retrieval date: 10/15/2009, IMS Date: )

Sourced from the National Library of Medicine. Abstract text and other information may be subject to copyright.

Comments and Corrections

CommentIn: Cancer Cell. 2009 Oct 6;16(4):270-1. (PMID: 19800569)

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MeSH headings (categories)

This article was linked to the MESH Headings shown below.

Animals Antineoplastic Agents - pharmacology Cell Differentiation - drug effects Cell Proliferation - drug effects Cell Survival - drug effects Dose-Response Relationship, Drug Gene Expression Profiling Gene Expression Regulation, Leukemic Genomics - methods HL-60 Cells Humans Inhibitory Concentration 50 Intracellular Signaling Peptides and Proteins - antagonists & inhibitors; genetics; metabolism Leukemia, Myeloid, Acute - drug therapy; genetics; metabolism; pathology Male Mice Mice, Inbred C57BL

Mice, Inbred C57BL Mice, Inbred NOD Mice, SCID Oxazines - pharmacology Phosphorylation Protein Kinase Inhibitors - pharmacology Protein-Tyrosine Kinases - antagonists & inhibitors; genetics; metabolism Proteomics - methods Pyridines - pharmacology Quinazolines - pharmacology RNA Interference Tandem Mass Spectrometry Time Factors Tumor Cells, Cultured Tyrosine U937 Cells Xenograft Model Antitumor Assays

Associated Chemicals: Antineoplastic Agents (0) ; Intracellular Signaling Peptides and Proteins (0) ; Oxazines (0) ; Protein Kinase Inhibitors (0) ; Pyridines (0) ; Quinazolines (0) ; R788 compound (0) ; gefitinib (184475-35-2) ; Tyrosine (55520-40-6) ; Protein-Tyrosine Kinases (EC 2.7.1.112) ; Syk kinase (EC 2.7.1.112)

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