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

Abstract

A fundamental challenge in treating disease is identifying molecular states that affect cellular responses to drugs. Here, we focus on 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 (e.g. 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 significant fraction (~35%) of the kinome, which includes ~50% of current, clinically relevant kinase-targeted drugs. Our results highlight an under-appreciated 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.

Highly multiplexed imaging of single cells using a high-throughput cyclic immunofluorescence method

“…However, 8–16 channel images already present an analytical challenge and most of our work is therefore concentrated on validating different panels of antibodies for 4–5 cycle CycIF. In this paper we demonstrate the application of CycIF to drug response at a single-cell level and show that multiplex single-cell measurement reveals new aspects of drug sensitivity and resistance 22 23 ; further refinement of the method will be reported at our web site at http://lincs.hms.harvard.edu/lin-NatCommun-2015 .…”

Diverse drug-resistance mechanisms can emerge from drug-tolerant cancer persister cells

“…We focused initially on identifying PERCs whose drug responses in combination treatment with erlotinib were strongly altered from PC9-1's drug response without erlotinib. There are a number of approaches to assess drug sensitivity from dose–response curves 17 22 23 24 . Here we chose to compute a sensitivity score based on signed-area differences between drug-response curves of PERCs versus PC9-1 that took into account replicate variability ( Fig.…”

Progress Towards a Public Chemogenomic Set for Protein Kinases and a Call for Contributions

“…Identification of a wellstudied kinase such as EGFR with drugs on the market and a number of compounds advancing in the clinic for other cancer indications, allows for potential repurposing, a faster way to approval. These and other examples [34][35][36][37][38][39][40][41][42][43][44] of PKIS applications demonstrate the utility of sharing an annotated kinase inhibitor set and convinced us to proceed with the construction of a comprehensive KCGS -one that provides coverage of the currently screenable kinome.…”