GSK-3 modulates cellular responses to a broad spectrum of kinase inhibitors.
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.
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Curtis A
CA
Thorne
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Chonlarat
C
Wichaidit
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Adam D
AD
Coster
Department of Biochemistry, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.
Bruce A
BA
Posner
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Lani F
LF
Wu
Green Center for Systems Biology, Simmons Cancer Center, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.|Department of Pharmaceutical Chemistry, University of California, San Francisco, San Francisco, CA 94158, USA.
Steven J
SJ
Altschuler
D000970:Antineoplastic Agents / Q000494:pharmacology; D018797:Cell Cycle Proteins / Q000037:antagonists & inhibitors; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004354:Drug Screening Assays, Antitumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000502:physiology*; D006801:Humans; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D011518:Proto-Oncogene Proteins / Q000037:antagonists & inhibitors; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors; D000097869:Polo-Like Kinase 1
D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D038362:Glycogen Synthase Kinase 3; D047428:Protein Kinase Inhibitors; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D058570:TOR Serine-Threonine Kinases; D000097869:Polo-Like Kinase 1