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 journalArticlepeer-review

21 Scopus citations

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

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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