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

Curtis A. Thorne, Chonlarat Wichaidit, Adam D. Coster, Bruce A. Posner, Lani F. Wu, Steven J. Altschuler

Research output: Contribution to journalArticle

18 Citations (Scopus)

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.

Original languageEnglish (US)
Pages (from-to)58-63
Number of pages6
JournalNature Chemical Biology
Volume11
Issue number1
DOIs
StatePublished - Jan 1 2015

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Glycogen Synthase Kinase 3
Phosphotransferases
Pharmaceutical Preparations
RNA Interference
Colorectal Neoplasms
Colon
Epithelial Cells
Phenotype
Cell Line

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

Cite this

Thorne, C. A., Wichaidit, C., Coster, A. D., Posner, B. A., Wu, L. F., & Altschuler, S. J. (2015). GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. Nature Chemical Biology, 11(1), 58-63. https://doi.org/10.1038/nchembio.1690

GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. / Thorne, Curtis A.; Wichaidit, Chonlarat; Coster, Adam D.; Posner, Bruce A.; Wu, Lani F.; Altschuler, Steven J.

In: Nature Chemical Biology, Vol. 11, No. 1, 01.01.2015, p. 58-63.

Research output: Contribution to journalArticle

Thorne, CA, Wichaidit, C, Coster, AD, Posner, BA, Wu, LF & Altschuler, SJ 2015, 'GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors', Nature Chemical Biology, vol. 11, no. 1, pp. 58-63. https://doi.org/10.1038/nchembio.1690
Thorne, Curtis A. ; Wichaidit, Chonlarat ; Coster, Adam D. ; Posner, Bruce A. ; Wu, Lani F. ; Altschuler, Steven J. / GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors. In: Nature Chemical Biology. 2015 ; Vol. 11, No. 1. pp. 58-63.
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