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Presentation Time: 4:25-4:45
Home University: UNC-Chapel Hill
Research Mentor: Dr. Lee M. Graves, Pharmacology
Program: CSF
Research Title: Activation of Mitochondrial Protease ClpP Inhibits mTOR Activity in Triple Negative Breast Cancer

ONC201 is an anti-cancer imipridone in clinical trials for multiple malignancies. Novel ONC201 analogues (the TR compounds) with greater potency were identified, although the anti-cancer mechanism of these drugs remained poorly understood. The Graves lab recently identified the mitochondrial caseinolytic protease (ClpP) as the target of these compounds and showed that ClpP activation was required for growth inhibition. Because the mTOR (mechanistic target of rapamycin) pathway plays a central role in regulating growth-related cellular processes including protein translation, nucleotide metabolism, and lipid synthesis, I analyzed the effects of TR57 treatment on the mTOR pathway in SUM159, a triple negative breast cancer model. Herein, I demonstrate that ClpP activation inhibits mTOR signaling as shown by loss of phosphorylation of mTOR substrates: eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), ribosomal protein S6 kinase (p70S6K), and ribosomal protein S6 (S6).  Thus, these results suggest that mTOR pathway inhibition may be involved in the reduction of protein synthesis and cell growth inhibition by ClpP activators.