Proteomic and genetic approaches identify Syk as an AML target.
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.
Department of Pediatric Oncology, Dana-Farber Cancer Institute and Children's Hospital Boston, Harvard Medical School, Boston, MA 02115, USA.
Cynthia K
CK
Hahn
Jacob E
JE
Berchuck
Kenneth N
KN
Ross
Rose M
RM
Kakoza
Karl
K
Clauser
Anna C
AC
Schinzel
Linda
L
Ross
Ilene
I
Galinsky
Tina N
TN
Davis
Serena J
SJ
Silver
David E
DE
Root
Richard M
RM
Stone
Daniel J
DJ
DeAngelo
Martin
M
Carroll
William C
WC
Hahn
Steven A
SA
Carr
Todd R
TR
Golub
Andrew L
AL
Kung
Kimberly
K
Stegmaier
D000631:Aminopyridines; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002454:Cell Differentiation / Q000187:drug effects*; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects; D004305:Dose-Response Relationship, Drug; D000077156:Gefitinib; D020869:Gene Expression Profiling; D015973:Gene Expression Regulation, Leukemic; D023281:Genomics / Q000379:methods; D018922:HL-60 Cells; D006801:Humans; D020128:Inhibitory Concentration 50; D047908:Intracellular Signaling Peptides and Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D009025:Morpholines; D010078:Oxazines / Q000494:pharmacology; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011505:Protein-Tyrosine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D040901:Proteomics / Q000379:methods; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines; D011799:Quinazolines / Q000494:pharmacology; D034622:RNA Interference; D000072377:Syk Kinase; D053719:Tandem Mass Spectrometry; D013997:Time Factors; D014407:Tumor Cells, Cultured; D014443:Tyrosine; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays
D000631:Aminopyridines; D000970:Antineoplastic Agents; D047908:Intracellular Signaling Peptides and Proteins; D009025:Morpholines; D010078:Oxazines; D047428:Protein Kinase Inhibitors; D011725:Pyridines; D011743:Pyrimidines; D011799:Quinazolines; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; C000606896:SYK protein, human; D000072377:Syk Kinase; C000606897:Syk protein, mouse; D000077156:Gefitinib; C523665:fostamatinib