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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE161574 | GEO | 2021/06/01

REPOSITORIES: GEO

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Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

Project description:By integration of transcriptome, CHIP-seq, ATAC-seq, proteomic and metabolite screening followed by carbon tracing (U-13C-Glucose, U-13C-Glutamine and U-13C-Palmitic acid) and extracellular flux analysis we provided evidence that genetic (shRNA and CRISPR/Cas9) and pharmacological (Alisertib) AURKA inhibition elicited substantial metabolic reprogramming supported in part by inhibition of MYC targets and concomitant activation of PPARA signaling. While glycolysis was suppressed by AURKA inhibition, we noted a compensatory increase in oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO). Whereas interference with AURKA elicited a suppression of c-Myc, we detected an upregulation of PGC1α, a master regulator of oxidative metabolism, upon AURKA inhibition. Chromatin immunoprecipitation experiments confirmed binding of c-Myc to the promoter region of PGC1α, which is abrogated by AURKA inhibition and in turn unleashed PGC1α expression. To interfere with this oxidative metabolic reprogramming, we combined AURKA inhibitors with inhibitors of FAO (etomoxir) and electron transport chain (gamitrinib) and found substantial synergistic growth inhibition in patient derived xenograft in vitro and extension of overall survival without induction of toxicity in normal tissue.

2021-06-01 | GSE161573 | GEO

Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

2021-06-01 | GSE161572 | GEO

AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:We described the metabolic alterations in glioblastoma model systems elicited by AURKA inhibition. By utilizing proteomic and transcriptomic analyses coupled with untargeted polar and nonpolar metabolite analysis by LC/MC, we found that AURKA inhibition leads to a profound reprogramming of tumor metabolism, which suppresses c-Myc protein levels and increases pro-survival PGC1α which in concert mediate a suppression of glycolysis and a concomitant activation of oxidative phosphorylation (OXPHOS) that is fueled by enhanced fatty acid oxidation (FAO). We targeted these metabolic aberrations with novel combination therapies involving clinical approved drugs in glioblastoma system both in vitro and in vivo. We used microarrays to detail the global programme of gene expression underlying cellularisation and identified distinct classes of up-regulated and down-regulated genes in Alisertib resistant cells.

2021-06-17 | GSE152612 | GEO

Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

| PRJNA678729 | ENA

Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

Project description:Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ATAC-Seq]

| PRJNA678735 | ENA

Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

Project description:Aurora A kinase Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma [ChIP-Seq]

| PRJNA678736 | ENA

AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

Project description:AURKA Inhibition Reprograms Metabolism dependent on PGC1α to Drive Synthetic Lethality with Fatty Acid Oxidation Inhibition in Glioblastoma

| PRJNA639824 | ENA

Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma.

Project description:Purpose: Glioblastoma remains a challenge in oncology, in part due to tumor heterogeneity.Experimental Design: Patient-derived xenograft and stem-like glioblastoma cells were used as the primary model systems.Results: Based on a transcriptome and subsequent gene set enrichment analysis (GSEA), we show by using clinically validated compounds that the combination of histone deacetylase (HDAC) inhibition and bromodomain protein (BRD) inhibition results in pronounced synergistic reduction in cellular viability in patient-derived xenograft and stem-like glioblastoma cells. Transcriptome-based GSEA analysis suggests that metabolic reprogramming is involved with synergistic reduction of oxidative and glycolytic pathways in the combination treatment. Extracellular flux analysis confirms that combined HDAC inhibition and BRD inhibition blunts oxidative and glycolytic metabolism of cancer cells, leading to a depletion of intracellular ATP production and total ATP levels. In turn, energy deprivation drives an integrated stress response, originating from the endoplasmic reticulum. This results in an increase in proapoptotic Noxa. Aside from Noxa, we encounter a compensatory increase of antiapoptotic Mcl-1 protein. Pharmacologic, utilizing the FDA-approved drug sorafenib, and genetic inhibition of Mcl-1 enhanced the effects of the combination therapy. Finally, we show in orthotopic patient-derived xenografts of GBM, that the combination treatment reduces tumor growth, and that triple therapy involving the clinically validated compounds panobinostat, OTX015, and sorafenib further enhances these effects, culminating in a significant regression of tumors in vivoConclusions: Overall, these results warrant clinical testing of this novel, efficacious combination therapy. Clin Cancer Res; 24(16); 3941-54. ©2018 AACR.

| S-EPMC6095717 | biostudies-literature

Allosteric inhibition of Aurora-A kinase by a synthetic vNAR domain.

Project description:The vast majority of clinically approved protein kinase inhibitors target the ATP-binding pocket directly. Consequently, many inhibitors have broad selectivity profiles and most have significant off-target effects. Allosteric inhibitors are generally more selective, but are difficult to identify because allosteric binding sites are often unknown or poorly characterized. Aurora-A is activated through binding of TPX2 to an allosteric site on the kinase catalytic domain, and this knowledge could be exploited to generate an inhibitor. Here, we generated an allosteric inhibitor of Aurora-A kinase based on a synthetic, vNAR single domain scaffold, vNAR-D01. Biochemical studies and a crystal structure of the Aurora-A/vNAR-D01 complex show that the vNAR domain overlaps with the TPX2 binding site. In contrast with the binding of TPX2, which stabilizes an active conformation of the kinase, binding of the vNAR domain stabilizes an inactive conformation, in which the αC-helix is distorted, the canonical Lys-Glu salt bridge is broken and the regulatory (R-) spine is disrupted by an additional hydrophobic side chain from the activation loop. These studies illustrate how single domain antibodies can be used to characterize the regulatory mechanisms of kinases and provide a rational basis for structure-guided design of allosteric Aurora-A kinase inhibitors.

| S-EPMC4967828 | biostudies-literature

High-Complexity shRNA Libraries and PI3 Kinase Inhibition in Cancer: High-Fidelity Synthetic Lethality Predictions.

Project description:Deregulated signal transduction is a cancer hallmark, and its complexity and interconnectivity imply that combination therapy should be considered, but large data volumes that cover the complexity are required in user-friendly ways. Here, we present a searchable database resource of synthetic lethality with a PI3 kinase signal transduction inhibitor by performing a saturation screen with an ultra-complex shRNA library containing 30 independent shRNAs per gene target. We focus on Ras-PI3 kinase signaling with T cell leukemia as a screening platform for multiple clinical and experimental reasons. Our resource predicts multiple combination-based therapies with high fidelity, ten of which we confirmed with small molecule inhibitors. Included are biochemical assays, as well as the IPI145 (duvelisib) inhibitor. We uncover the mechanism of synergy between the PI3 kinase inhibitor GDC0941 (pictilisib) and the tubulin inhibitor vincristine and demonstrate broad synergy in 28 cell lines of 5 cancer types and efficacy in preclinical leukemia mouse trials.

| S-EPMC6690758 | biostudies-literature

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