ONC212 is a fluorinated imipridone with preclinical efficacy against pancreatic and other
malignancies. Although mitochondrial
protease ClpP was identified as an ONC212-binding target, the mechanism leading to
cancer cell death is incompletely understood. We investigated
mitochondrial dysfunction and metabolic rewiring triggered by
ONC212 in
pancreatic cancer, a deadly
malignancy with an urgent need for novel
therapeutics. We found ClpP is expressed in
pancreatic cancer cells and is required for
ONC212 cytotoxicity. ClpX, the regulatory binding partner of ClpP, is suppressed upon
ONC212 treatment. Immunoblotting and extracellular flux analysis showed
ONC212 impairs oxidative phosphorylation (OXPHOS) with decrease in mitochondrial-derived
ATP production. Although collapse of mitochondrial function is observed across ONC212-treated cell lines, only OXPHOS-dependent cells undergo apoptosis. Cells relying on glycolysis undergo growth arrest and upregulate
glucose catabolism to prevent ERK1/2 inhibition and apoptosis.
Glucose restriction or combination with glycolytic inhibitor
2-deoxy-D-glucose synergize with
ONC212 and promote apoptosis in vitro and in vivo Thus,
ONC212 is a novel mitocan targeting oxidative metabolism in
pancreatic cancer, leading to different cellular outcomes based on divergent metabolic programs.