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

Nature Chemical Biology volume 11, pages 58–63 (2015)Cite this article

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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.

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Figure 1: Decreased GSK-3 activity alters cellular response to oncology drugs and kinase inhibitors.
Figure 2: GSK-3 inhibition desensitizes cells to mTOR inhibitors.
Figure 3: GSK-3 inhibition sensitizes cells to PLK1 inhibitors.
Figure 4: CRC cell lines are intrinsically more resistant to mTOR inhibitors and sensitive to PLK1 inhibitors.
Figure 5: GSK-3 interacts with the kinome to control cell proliferation.
Figure 6: Summary of drug-targeted kinases affected by GSK-3 activity.

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Acknowledgements

We thank M. Cobb and members of the Altschuler and Wu laboratories for critical reading of the manuscript; J. Shay (University of Texas Southwestern) for providing the HCEC cell line and guidance on culture techniques, M. Ramirez for experimental support and J. Life for help with high-throughput screening experiments. This research was supported by a Cancer Biology Training Grant T32 CA124334 (C.A.T.), an American Cancer Society–Lakeshore Division Postdoctoral Fellowship (C.A.T.), the National Institute of Health grants K99 DK103126-01 (C.A.T.), CA133253 (S.J.A.), CA184984 (L.F.W.), R01 GM081549 (L.F.W.), CPRIT RP10900 (L.F.W.), and the Welch Foundation I-1619 (S.J.A.) and I-1644 (L.F.W.).

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Author notes

  1. Curtis A Thorne and Chonlarat Wichaidit: These authors contributed equally to this work.

Authors and Affiliations

  1. Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Curtis A Thorne, Chonlarat Wichaidit, Adam D Coster, Lani F Wu & Steven J Altschuler

  2. Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, Texas, USA

    Bruce A Posner

  3. Department of Pharmaceutical Chemistry, University of California–San Francisco, San Francisco, California, USA

    Lani F Wu & Steven J Altschuler

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  1. Curtis A Thorne
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Contributions

C.A.T. designed, performed and analyzed experiments. C.W. designed experiments and performed analysis of data. A.D.C. aided in analysis of data. B.A.P. designed HTS experiments and provided critical reagents. C.A.T., C.W., L.F.W. and S.J.A. wrote the manuscript with advice from all authors. L.F.W. and S.J.A. guided all aspects of this study.

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Correspondence to Lani F Wu or Steven J Altschuler.

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Supplementary information

Supplementary Text and Figures

Supplementary Results, Supplementary Figures 1–10, Supplementary Table 1 and Supplementary Notes 1–4 (PDF 2419 kb)

Supplementary Data Set 1

DrugBank gene in kinome list (XLSX 118 kb)

Supplementary Data Set 2

Oncology set (XLSX 27 kb)

Supplementary Data Set 3

PKIS (XLS 234 kb)

Supplementary Data Set 4

RNAi (XLSX 26 kb)

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Thorne, C., Wichaidit, C., Coster, A. et al. GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. Nat Chem Biol 11, 58–63 (2015). https://doi.org/10.1038/nchembio.1690

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