ArticleClinical cancer research : an official journal of the American Association for Cancer Research2022
Induction of Synthetic Lethality by Activation of Mitochondrial ClpP and Inhibition of HDAC1/2 in Glioblastoma.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 29 papers.
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Who cites it
29 citing papers in PubMed, 29 citations in OpenAlex.
- ONC201/dordaviprone for H3 K27M-mutant tumors: Discovery, mechanisms, therapeutic potential, and future directions.Genes & diseases · 2027Review
- The histone deacetylase family in health and disease.Signal transduction and targeted therapy · 2026Review
- Deciphering LonP1's role in glioblastoma: an alternative mechanism of treatment resistance.American journal of physiology. Cell physiology · 2026Article
- Small molecule activators of the mitochondrial protease ClpP induce senescence in triple-negative breast cancer cells and sensitize cells to the Bcl-2 inhibitor venetoclax.Cell death & disease · 2026Article
- The role of dordaviprone in the multidisciplinary management of diffuse midline glioma.Surgical neurology international · 2026Review
- Small Molecule Activators of the Mitochondrial Protease ClpP Induce Senescence in Triple-Negative Breast Cancer Cells and Sensitize Cells to the Bcl-2 Inhibitor Venetoclax.Research square · 2025Article
- Recent advances in the design of small molecules targeting human ClpP.Future medicinal chemistry · 2025Review
- Mitochondrial Protease ClpP: Cancer Marker and Drug Target.Pharmaceuticals (Basel, Switzerland) · 2025Review
- Targeting the Mitochondria in High-Grade Gliomas.Cancers · 2025Review
- Combination of the First-in-Class Imipridone ONC201 and Standard Anticancer Therapies as a Rational Approach for Therapeutic Benefit.Current issues in molecular biology · 2025Review
- Towards Effective Treatment of Glioblastoma: The Role of Combination Therapies and the Potential of Phytotherapy and Micotherapy.Current issues in molecular biology · 2024Review
- The Role and Applied Value of Mitochondria in Glioma-Related Research.CNS neuroscience & therapeutics · 2024Review
- Targeting Mitochondria in Glioma: New Hopes for a Cure.Biomedicines · 2024Review
- ONC212, alone or in synergistic conjunction with Navitoclax (ABT-263), promotes cancer cell apoptosis via unconventional mitochondrial-independent caspase-3 activation.Cell communication and signaling : CCS · 2024Article
- ONC206 targeting ClpP induces mitochondrial dysfunction and protective autophagy in hepatocellular carcinoma cells.Neoplasia (New York, N.Y.) · 2024Article
- Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies.Biomedicines · 2024Review
- A review of current therapeutics targeting the mitochondrial protease ClpP in diffuse midline glioma, H3 K27-altered.Neuro-oncology · 2024Review
- HSPA8-mediated stability of the CLPP protein regulates mitochondrial autophagy in cisplatin-resistant ovarian cancer cells.Acta biochimica et biophysica Sinica · 2024Article
- OGDH and Bcl-xL loss causes synthetic lethality in glioblastoma.JCI insight · 2024Article
- Review
Corrections and comments
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Authors and funding
11 authors at 4 institutions in 2 countries.
Funding
Abstract
purposeNovel therapeutic targets are critical to unravel for the most common primary brain tumor in adults, glioblastoma (GBM). We have identified a novel synthetic lethal interaction between ClpP activation and HDAC1/2 inhibition that converges on GBM energy metabolism. EXPERIMENTAL
designTranscriptome, metabolite, and U-13C-glucose tracing analyses were utilized in patient-derived xenograft (PDX) models of GBM. Orthotopic GBM models were used for in vivo studies.
resultsWe showed that activation of the mitochondrial ClpP protease by mutant ClpP (Y118A) or through utilization of second-generation imipridone compounds (ONC206 and ONC212) in combination with genetic interference of HDAC1 and HDAC2 as well as with global (panobinostat) or selective (romidepsin) HDAC inhibitors caused synergistic reduction of viability in GBM model systems, which was mediated by interference with tricarboxylic acid cycle activity and GBM cell respiration. This effect was partially mediated by activation of apoptosis along with activation of caspases regulated chiefly by Bcl-xL and Mcl-1. Knockdown of the ClpP protease or ectopic expression of a ClpP D190A mutant substantially rescued from the inhibition of oxidative energy metabolism as well as from the reduction of cellular viability by ClpP activators and the combination treatment, respectively. Finally, utilizing GBM PDX models, we demonstrated that the combination treatment of HDAC inhibitors and imipridones prolonged host survival more potently than single treatments or vehicle in vivo.
conclusionsCollectively, these observations suggest that the efficacy of HDAC inhibitors might be significantly enhanced through ClpP activators in model systems of human GBM.
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Registered trials
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