TY - JOUR
T1 - GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors
AU - Thorne, Curtis A.
AU - Wichaidit, Chonlarat
AU - Coster, Adam D.
AU - Posner, Bruce A.
AU - Wu, Lani F.
AU - Altschuler, Steven J.
N1 - Funding Information:
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.).
Publisher Copyright:
© 2015 Nature America, Inc. All rights reserved.
PY - 2015/1/1
Y1 - 2015/1/1
N2 - 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.
AB - 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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U2 - 10.1038/nchembio.1690
DO - 10.1038/nchembio.1690
M3 - Article
C2 - 25402767
AN - SCOPUS:84927136638
SN - 1552-4450
VL - 11
SP - 58
EP - 63
JO - Nature chemical biology
JF - Nature chemical biology
IS - 1
ER -