2. Academic Validation
  3. PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells

PP2A-based triple-strike therapy overcomes mitochondrial apoptosis resistance in brain cancer cells

  • Mol Oncol. 2023 Jul 17. doi: 10.1002/1878-0261.13488.
Oxana V Denisova 1,  Joni Merisaari 1 2,  Riikka Huhtaniemi 1,  Xi Qiao 1,  Laxman Yetukuri 1 3 4,  Mikael Jumppanen 1,  Amanpreet Kaur 1,  Mirva Pääkkönen 1,  Сarina von Schantz-Fant 3,  Michael Ohlmeyer 5 6,  Krister Wennerberg 3 7,  Otto Kauko 1,  Raphael Koch 8,  Tero Aittokallio 3 4 9,  Mikko Taipale 10,  Jukka Westermarck 1 2
Affiliations

Affiliations

  • 1 Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland.
  • 2 Institute of Biomedicine, University of Turku, Turku, Finland.
  • 3 Institute for Molecular Medicine Finland (FIMM), HiLIFE, University of Helsinki, Helsinki, Finland.
  • 4 Centre for Biostatistics and Epidemiology (OCBE), University of Oslo, Oslo, Norway.
  • 5 Icahn School of Medicine at Mount Sinai, NY, USA.
  • 6 Atux Iskay LLC, Plainsboro, NJ, USA.
  • 7 Biotech Research & Innovation Centre, University of Copenhagen, Copenhagen, Denmark.
  • 8 University Medical Center Göttingen, Göttingen, Germany.
  • 9 Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
  • 10 Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Canada.
PMID: 37458534 DOI: 10.1002/1878-0261.13488
Abstract

Mitochondrial glycolysis and hyperactivity of the phosphatidylinositol 3-kinase (PI3K)-protein kinase B (Akt) pathway are hallmarks of malignant brain tumors. However, kinase inhibitors targeting Akt (AKTi) or the glycolysis master regulator pyruvate dehydrogenase kinase (PDKi) have failed to provide clinical benefits for brain tumor patients. Here, we demonstrate that heterogenous glioblastoma (GB) and medulloblastoma (MB) cell lines display only cytostatic responses to combined Akt and PDK targeting. Biochemically, the combined Akt and PDK inhibition resulted in the shutdown of both target pathways and priming to mitochondrial Apoptosis but failed to induce Apoptosis. In contrast, all tested brain tumor cell models were sensitive to a triplet therapy, in which Akt and PDK inhibition was combined with the pharmacological reactivation of protein Phosphatase 2A (PP2A) by NZ-8-061 (also known as DT-061), DBK-1154 and DBK-1160. We also provide proof-of-principle evidence for in vivo efficacy in the intracranial GB and MB models by the brain-penetrant triplet therapy (AKTi + PDKi + PP2A reactivator). Mechanistically, PP2A reactivation converted the cytostatic AKTi + PDKi response to cytotoxic Apoptosis, through PP2A-elicited shutdown of compensatory mitochondrial Oxidative Phosphorylation and by increased proton leakage. These results encourage the development of triple-strike strategies targeting Mitochondrial Metabolism to overcome therapy tolerance in brain tumors.

Keywords

AKT; PDK; PP2A; apoptosis; glioblastoma; mitochondria.

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