Identification of GSK3 as a primary
target of IMiDs and biomarker of
clinical response using Drosophila
Suzanne Trudel, Sam E. Scanga, , Fabrizio G.
Mastronardi, Ellen N. Wei, Frank Mercurio, Antonia
LopezGirona, Svetlana Gaidarova, David Webb,
Christine Chen, A. Keith Stewart and Armen S.
Manoukian
Disclosures
· CC, AKS, AM Grant funding: Celgene
· ST, CC, AKS Speakers Bureau: Celgene
· ST, CC, AKS Honoriums: Celgene
· FM, ALG, SG, DW Employees of Celgene
1
Thalidomide and IMiDs: Mechanisms of Action (MOA)
· Preclinical studies have revealed multiple direct and indirect antitumor activities
Hideshima T, et al. Nature Reviews Cancer 7, 585598 (August 2007)
· Recent studies have identified cerebron (CRBN) as a putative target of thalidomide
induced teratogenicity
· A unifying molecular MOA to explain the pleiotropic antitumor activity has not yet
been clearly defined
Drug Discovery Platform in Drosophila
Larval Imaginal Discs
wingless protein
Distalless protein
signal
effector
Adult fly wing
Drosophila life cycle
Final structure
· Mechanism of Action elucidation
· Library screening for new compound identification
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Thalidomide Feeding Phenocopies Wg Pathway Mutant
Phenotype
DMSO Thal
Wnt/Wg Signaling Pathway
3
IMiD Effects are Downstream of dAxin and Sgg/GSK3
IMiDs Disrupt Apical Localization of Sgg/GSK3
Sgg
Tubulin
DAPI
4
Sgg/GSK3 is a Component of the BiotinIMiD
Binding Complex In Vivo
Proposed Model of Thalidomide and IMiD
Targeting In Drosophila
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IMiDs Disrupt GSK3 Localization in Myeloma Cells
GSK3 is Required for IMiD Activity in Myeloma Cells
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IMiDs Fail to Induce GSK3 Nuclear Localization in
IMiD Resistant Cells
MY5 MY5.1R MY5.2R
MY5 MY5.1R
GSK3 Localization Predicts for Lenalidomide Response in CLL
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Conclusions:
· GSK3 is required for thalidomide and IMiD activity
· modulation of GSK3 activity by subcellular
relocalization may account for the pleiotropic anticancer
and teratogenic activity of IMiDs
· GSK3 localization is potential biomarker for IMiD
resistance
Acknowledgements
Princess Margaret Hospital
(Trudel Laboratory)
Zhi Hua Li
Mayo Clinic Scottsdale
Ellen Wei
Keith A. Stewart
Clinical
Celgene
Christine Chen
Frank Mercurio,
Antonia Lopez-Girona,
OCI (Drosophila)
Svetlana Gaidarova,
Armen Manoukian
David Webb
Sam Scanga
Fabrizio G. Mastronardi
The Ontario Institute for Cancer Research
Grant Support from Celgene
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IMiDS Reverse the Ectopic/Apical Localization of
Sgg/GSK3 in dAxin Mutant cells
Axin mutant cells
merge
GFP
GSK-3
DMSO
Thal
CC-4047
40 m
IMiD Treatment Upregulates the GSK3 Substrate, p27
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