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Metabolic re-programming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities

ABSTRACT: Gene expression levels were determined with control or PD-0332991 treatment

ORGANISM(S): Homo sapiens

PROVIDER: GSE75979 | GEO | 2015/12/21

SECONDARY ACCESSION(S): PRJNA305887

REPOSITORIES: GEO

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Metabolic re-programming of pancreatic cancer mediated by CDK4/6 inhibition elicits unique vulnerabilities

Project description:Gene expression levels were determined with control or PD-0332991 treatment CAPAN2 Cells were subject to DMSO/ PD-0332991 treatment. RNA was harvested at 72 hours post treatment and analyzed on Illumina microarrays

2015-12-21 | E-GEOD-75979 | biostudies-arrayexpress

Metabolic Reprogramming of Pancreatic Cancer Mediated by CDK4/6 Inhibition Elicits Unique Vulnerabilities.

Project description:Due to loss of p16ink4a in pancreatic ductal adenocarcinoma (PDA), pharmacological suppression of CDK4/6 could represent a potent target for treatment. In PDA models, CDK4/6 inhibition had a variable effect on cell cycle but yielded accumulation of ATP and mitochondria. Pharmacological CDK4/6 inhibitors induce cyclin D1 protein levels; however, RB activation was required and sufficient for mitochondrial accumulation. CDK4/6 inhibition stimulated glycolytic and oxidative metabolism and was associated with an increase in mTORC1 activity. MTOR and MEK inhibitors potently cooperate with CDK4/6 inhibition in eliciting cell-cycle exit. However, MTOR inhibition fully suppressed metabolism and yielded apoptosis and suppression of tumor growth in xenograft models. The metabolic state mediated by CDK4/6 inhibition increases mitochondrial number and reactive oxygen species (ROS). Concordantly, the suppression of ROS scavenging or BCL2 antagonists cooperated with CDK4/6 inhibition. Together, these data define the impact of therapeutics on PDA metabolism and provide strategies for converting cytostatic response to tumor cell killing.

| S-EPMC4757440 | biostudies-literature

CDK4/6 inhibitors in ER positive breast cancers

Project description:Gene expression levels were determined with control or PD-0332991 treatment MCF7, T47D cells were subject to DMSO/ PD-0332991 treatment . RNA was harvested at 120 hours post treatment and analyzed on Illumina microarrays

2016-08-01 | E-GEOD-80987 | biostudies-arrayexpress

CDK4/6 inhibitors in ER positive breast cancers

Project description:Gene expression levels were determined with control or PD-0332991 treatment

2016-08-01 | GSE80987 | GEO

Gene expression profiling of HepG2 cells after treatment of PD-0332991 and CDK4-6 Knockdown

Project description:The aim of this study is to estimate gene expression variations involved in glucose meatbolism in HepG2 cell line after cell cycle(G1 to S phase) inhibition by using drug(PD-0332991) or CDK4-6-knock down. We hypothesized that transition of glycolytic gene expression might indicates the effect of PD-0332991 drug treatment in Hepatocellular carcinoma cells.

2020-02-18 | GSE145389 | GEO

Effects of PD-0332991 on gene expression of human pancreatic ductal adenocarcinoma (PDAC) cell lines

Project description:PD-0332991 is a small molecule inhibitor for Cdk4 and Cdk6. It exerted growth inhibitory effects on PDAC cell lines (AsPC-1 and COLO-357). Microarray analysis was used to characterize the changes in gene expression profiles of AsPC-1 and COLO-357 upon PD-0332991 incubation AsPC-1 and COLO-357 cells were treated in the absence or presence of 5 ÂµM PD-0332991 for 24 h and 72 h. Each expreimental condition had biological triplicates. Twenty-four samples were analyzed in total.

2012-10-10 | E-GEOD-39646 | biostudies-arrayexpress

Effects of PD-0332991 on gene expression of human pancreatic ductal adenocarcinoma (PDAC) cell lines

2012-10-10 | GSE39646 | GEO

Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma.

Project description:Purpose: The goal of this study is to enhance the efficacy of imipridones, a novel class of AKT/ERK inhibitors that displayed limited therapeutic efficacy against glioblastoma (GBM).Experimental Design: Gene set enrichment, LC/MS, and extracellular flux analyses were used to determine the mechanism of action of novel imipridone compounds, ONC206 and ONC212. Orthotopic patient-derived xenografts were utilized to evaluate therapeutic potency.Results: Imipridones reduce the proliferation of patient-derived xenograft and stem-like glioblastoma cell cultures in vitro and in multiple xenograft models in vivo ONC212 displayed the highest potency. High levels of c-myc predict susceptibility to growth inhibition and apoptosis induction by imipridones and increased host survival in orthotopic patient-derived xenografts. As early as 1 hour, imipridones elicit on-target inhibition, followed by dephosphorylation of GSK3? at serine 9. GSK3? promotes phosphorylation of c-myc at threonine 58 and enhances its proteasomal degradation. Moreover, inhibition of c-myc by BRD4 antagonists sensitizes for imipridone-induced apoptosis in stem-like GBM cells in vitro and in vivo Imipridones affect energy metabolism by suppressing both glycolysis and oxidative phosphorylation, which is accompanied by a compensatory activation of the serine-one carbon-glycine (SOG) pathway, involving the transcription factor ATF4. Interference with the SOG pathway through novel inhibitors of PHGDH results in synergistic cell death induction in vitro and in vivo Conclusions: These results suggest that c-myc expression predicts therapeutic responses to imipridones and that imipridones lead to suppression of tumor cell energy metabolism, eliciting unique metabolic vulnerabilities that can be exploited for clinical relevant drug combination therapies. Clin Cancer Res; 24(21); 5392-406. ©2018 AACR.

| S-EPMC6214769 | biostudies-literature

Aurora kinase A inhibition reverses the Warburg effect and elicits unique metabolic vulnerabilities in glioblastoma.

Project description:Aurora kinase A (AURKA) has emerged as a drug target for glioblastoma (GBM). However, resistance to therapy remains a critical issue. By integration of transcriptome, chromatin immunoprecipitation sequencing (CHIP-seq), Assay for Transposase-Accessible Chromatin sequencing (ATAC-seq), proteomic and metabolite screening followed by carbon tracing and extracellular flux analyses we show that genetic and pharmacological AURKA inhibition elicits metabolic reprogramming mediated by inhibition of MYC targets and concomitant activation of Peroxisome Proliferator Activated Receptor Alpha (PPARA) signaling. While glycolysis is suppressed by AURKA inhibition, we note an increase in the oxygen consumption rate fueled by enhanced fatty acid oxidation (FAO), which was accompanied by an increase of Peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC1α). Combining AURKA inhibitors with inhibitors of FAO extends overall survival in orthotopic GBM PDX models. Taken together, these data suggest that simultaneous targeting of oxidative metabolism and AURKAi might be a potential novel therapy against recalcitrant malignancies.

| S-EPMC8410792 | biostudies-literature

Cdk4 is a critical regulator of age-associated hepatic steatosis.

Project description:Purpose: to identify the impact of cdk4 inhibition on genes and pathways involved in age-associated liver disorders using next generation sequencing on young and control- or PD0332991-treated aged mice. Methods: RNA was isolated from livers of young (2 month old) and old (20-22 month old) C57Bl6 mice. Old mice were either either control-aged mice or PD-0332991 treated aged mice (450mg/dk for 2 weeks). The three conditions were represented in triplicate. Raw reads passing quality filtration were aligned to the mm10 mouse genome using UCSC annotations by pseudoalignment in Kallisto. All reasonably expressed transcripts were submitted for statistical analysis to identify age-altered transcripts corrected by cdk4 inhibition. Results: We mapped a minimum of 20 million reads per sample, which corresponded to a total of 25,240 transcripts. Of these, 12,551 were considered reasonably expressed and were included in analysis comparing control-aged v young and PD0332991-treated-aged v young. Conclusion: Inhibition of cdk4 in ages wildtype mice by cdk4 inhibitor PD-0332991 reduces CEBPa-p300 and reduced aged-related alterations of hepatic structure and function.

2018-04-01 | GSE104395 | GEO

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