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

ABSTRACT: 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.

SUBMITTER: Ishida CT

PROVIDER: S-EPMC6214769 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature

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

Ishida Chiaki T CT Zhang Yiru Y Bianchetti Elena E Shu Chang C Nguyen Trang T T TTT Kleiner Giulio G Sanchez-Quintero Maria J MJ Quinzii Catarina M CM Westhoff Mike-Andrew MA Karpel-Massler Georg G Prabhu Varun V VV Allen Joshua E JE Siegelin Markus D MD

Clinical cancer research : an official journal of the American Association for Cancer Research 20180723 21

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 pro ...[more]

PMID: 30037819

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Project description:The receptor kinase c-MET has emerged as a target for glioblastoma therapy. However, treatment resistance emerges inevitably. Here, we performed global metabolite screening with metabolite set enrichment coupled with transcriptome and gene set enrichment analysis and proteomic screening, and identified substantial reprogramming of tumor metabolism involving oxidative phosphorylation and fatty acid oxidation (FAO) with substantial accumulation of acyl-carnitines accompanied by an increase of PGC1α in response to genetic (shRNA and CRISPR/Cas9) and pharmacologic (crizotinib) inhibition of c-MET. Extracellular flux and carbon tracing analyses (U-13C-glucose, U-13C-glutamine, and U-13C-palmitic acid) demonstrated enhanced oxidative metabolism, which was driven by FAO and supported by increased anaplerosis of glucose carbons. These findings were observed in concert with increased number and fusion of mitochondria and production of reactive oxygen species. Genetic interference with PGC1α rescued this oxidative phenotype driven by c-MET inhibition. Silencing and chromatin immunoprecipitation experiments demonstrated that cAMP response elements binding protein regulates the expression of PGC1α in the context of c-MET inhibition. Interference with both oxidative phosphorylation (metformin, oligomycin) and β-oxidation of fatty acids (etomoxir) enhanced the antitumor efficacy of c-MET inhibition. Synergistic cell death was observed with c-MET inhibition and gamitrinib treatment. In patient-derived xenograft models, combination treatments of crizotinib and etomoxir, and crizotinib and gamitrinib were significantly more efficacious than single treatments and did not induce toxicity. Collectively, we have unraveled the mechanistic underpinnings of c-MET inhibition and identified novel combination therapies that may enhance its therapeutic efficacy. SIGNIFICANCE: c-MET inhibition causes profound metabolic reprogramming that can be targeted by drug combination therapies.

Dataset Information

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

Publications

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

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