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RNA-seq of prostate cancer cell lines with acquired resistance to AKT inhibitors GDC-0068 (ATP competitive) or MK206 (allosteric)

ABSTRACT: Goal: Study resistance mechanisms to ATP-competitive vs. allosteric AKT inhibitors, in prostate cancer Methods: RNA-sequencing Results: Resistance to the ATP-competitive inhibitor GDC-0068 was driven by compensatory activity of parallel signaling pathways

ORGANISM(S): Homo sapiens

PROVIDER: GSE139178 | GEO | 2020/01/24

REPOSITORIES: GEO

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RNA-seq of prostate cancer cell lines with acquired resistance to AKT inhibitors GDC-0068 (ATP competitive) or MK206 (allosteric)

Project description:RNA-seq of prostate cancer cell lines with acquired resistance to AKT inhibitors GDC-0068 (ATP competitive) or MK206 (allosteric)

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GCN2 kinase Activation by ATP-competitive Kinase Inhibitors

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Transcriptional profiling of ATP-competitive mTOR inhibitors reveals mTORC1 and mTORC2 specific regulatory networks

Project description:The mammalian target of rapamycin (mTOR) is a central regulator of cell growth and proliferation in response to growth factor and nutrient signaling. Consequently, this kinase is implicated in metabolic diseases including cancer and diabetes so there is great interest in understanding mTOR regulatory networks. mTOR exists in two functionally distinct complexes, mTORC1 and mTORC2, and whereas the natural product rapamycin only inhibits a subset of mTORC1 functions, recently developed ATP-competitive mTOR inhibitors have revealed new roles for both complexes. To examine the complete spectrum of mTOR responsive cellular processes, we compared the transcriptional profiles of mammalian cells treated with rapamycin versus the ATP-competitive inhibitor PP242. Our analysis provides a genome-wide view of the transcriptional outputs of mTOR signaling that are insensitive to rapamycin. Gene expression in mouse NIH3T3 cells was measured after 18 hour treatment with DMSO (control), 50 nM rapamycin, or 2 uM PP242. Four independent experiments were performed for each condition.

2011-03-15 | E-GEOD-27784 | biostudies-arrayexpress

HDX-MS Analysis of Conformation Selection by ATP-competitive Inhibitors and Allosteric Communication in ERK2

Project description:Activation of the extracellular signal regulated kinase-2 (ERK2) by phosphorylation has been shown to involve changes in protein dynamics, as determined by hydrogen-deuterium exchange mass spectrometry (HDX-MS) and NMR relaxation dispersion measurements. These can be described by a global exchange between two conformational states, named “L” and “R”, where R is associated with a catalytically productive ATP-binding mode. An ATP-competitive ERK1/2 inhibitor, Vertex-11e, has properties of conformation selection for the R-state, revealing movements of the activation loop that are allosterically coupled to the kinase active site. However, the features of inhibitors important for R-state selection are unknown. Here we survey a panel of ATP-competitive ERK inhibitors using HDX-MS and NMR and identify 14 new molecules with properties of R-state selection. They reveal effects propagated to distal regions in the P+1 and helix αF segments surrounding the activation loop, as well as helix αL16. Crystal structures of inhibitor complexes with ERK2 reveal systematic shifts in the Gly loop and helix αC, mediated by a Tyr-Tyr ring stacking interaction and the conserved Lys-Glu salt bridge. The findings suggest a model for the R-state involving small movements in the N-lobe that promote compactness within the kinase active site and alter mobility surrounding the activation loop. Such properties of conformation selection might be exploited to modulate the protein docking interface used by ERK substrates and effectors.

2024-03-20 | PXD048311 | Pride

Project description:Distinct resistance mechanisms arise to allosteric vs. ATP-competitive AKT inhibitors

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ATP-Competitive Partial Antagonists—'PAIR's—Segregate IRE1α’s RNase-Mediated Biological Outputs

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Charaterization of genetic alterations and gene expression signatures found in BCR-ABL inhibitor-resistant KCL-22 subpopulations and single clones

Project description:KCL-22 is a chronic myeloid leukemia (CML) cell line derived from a patient in blast crisis phase and harbors the BCR-ABL translocation. The catalytic (ATP-competitive) BCR-ABL inhibitors imatinib and nilotinib have dramatically improved CML patient outcome, but the development of resistance remains a clinical challenge. The recent identification of allosteric BCR-ABL inhibitors, such as GNF-2, which target the enzyme by binding to the myristoyl pocket rather than catalytic site of ABL1, may provide a strategy to broadly overcome resistance to the class of ABL1 ATP competitive inhibitors. We therefore wanted to use the ClonTracer barcoding system to compare the clonal responses of KCL-22 to imatinib, nilotinib and GNF-2. RNA-seq was employed to characterize genetic alterations and gene expression signatures in the pooled cell populations resistant to BCR-ABL inhibitors as well as single clones showing differential response to the three inhibitors. mRNA profiling of the subpopulations and single clones of human CML cell line KCL-22 that contribute to BCR-ABL inhibitor resistance

2014-10-07 | E-GEOD-62121 | biostudies-arrayexpress

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