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Nat Chem Biol. 2015 Jan;11(1):58-63. doi: 10.1038/nchembio.1690. Epub 2014 Nov 17.

GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors.

Author information

1
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
2
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
3
Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
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Contributed equally

Abstract

A fundamental challenge in treating disease is identifying molecular states that affect cellular responses to drugs. Here, we focus on glycogen synthase kinase 3 (GSK-3), a key regulator for many of the hallmark behaviors of cancer cells. We alter GSK-3 activity in colon epithelial cells to test its role in modulating drug response. We find that GSK-3 activity broadly affects the cellular sensitivities to a panel of oncology drugs and kinase inhibitors. Specifically, inhibition of GSK-3 activity can strongly desensitize or sensitize cells to kinase inhibitors (for example, mTOR or PLK1 inhibitors, respectively). Additionally, colorectal cancer cell lines, in which GSK-3 function is commonly suppressed, are resistant to mTOR inhibitors and yet highly sensitive to PLK1 inhibitors, and this is further exacerbated by additional GSK-3 inhibition. Finally, by conducting a kinome-wide RNAi screen, we find that GSK-3 modulates the cell proliferative phenotype of a large fraction (∼35%) of the kinome, which includes ∼50% of current, clinically relevant kinase-targeted drugs. Our results highlight an underappreciated interplay of GSK-3 with therapeutically important kinases and suggest strategies for identifying disease-specific molecular profiles that can guide optimal selection of drug treatment.

PMID:
25402767
PMCID:
PMC4270937
DOI:
10.1038/nchembio.1690
[Indexed for MEDLINE]
Free PMC Article

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