Abstract 672: ABTL0812, a new antitumor drug that inhibits the axis Akt/mTOR through a novel mechanism of action

Background: ABTL0812 is a first-in-class orally administered compound currently in Phase I/Ib First in Human Clinical Trial in patients with advanced solid tumors (NCT02201823). ABTL0812 has cytotoxic effect on a wide range of human tumor cell lines, including those which have become resistant to standard therapy. We hereby dissect the anti-tumor activity of ABTL0812, which relies on a novel mechanism of action that promotes inhibition of the Akt/mTOR axis in cancer cells. Material & methods: ABTL0812 molecular targets were identified by in silico analysis, comparing ABTL0812 chemical structure against a database including more than one million receptor-ligand interaction data. Functional relevance of the targets was confirmed biochemically and pharmacologically. ABTL0812 mechanism of action was established using human lung and pancreatic tumor cells, MEF KO cells, as well as tumor xenografts. Results: In silico screening showed that ABTL0812 binds four targets which regulate tumor progression through Akt/mTOR axis. Two of them are the transcription factors PPARα and PPARγ (Peroxisome-Proliferator Activating Receptors). In lung and pancreatic tumor cells ABTL0812 activated PPARα/γ-dependent gene transcription, while pharmacological inhibition with PPARα/γ antagonists impaired ABTL0812 cytotoxic effect. Interestingly, ABTL0812 induced transcription of the endogenous Akt inhibitor TRIB3 (tribbles homologue 3) through PPARα/γ activation. TRIB3 is a pseudokinase that inhibits Akt by direct binding and preventing its phosphorylation by mTORC2 complex. According to this, ABTL0812-induced TRIB3 overexpression resulted in inhibition of Akt phosphorylation, impaired phosphorylation of the Akt substrates TSC2 and PRAS40 and mTORC1 inhibition (pS6), which in turn promoted autophagy-mediated tumor cell death. MEF TRIB3-/- cells were resistant to ABTL0812-induced cell death, indicating that TRIB3 mediates ABTL0812 citotoxicity. Finally, Akt inhibition was observed in human lung and pancreatic tumor xenograft models treated with ABTL0812 and in human platelets incubated with ABTL0812. This supported the rational for using Akt phosphorylation as a pharmacodynamic biomarker to monitor activity of ABTL0812 in patients included in the Clinical Trial. Conclusion: ABTL0812 promotes autophagy-mediated cell death in different cancer paradigms by inhibiting the Akt/mTOR axis through a novel mechanism of action. ABTL0812 induces PPARα/γ-mediated transcription of the TRIB3 gene. Upregulated TRIB3 protein binds and inhibits Akt, leading to mTORC1 inhibition and reduction of tumor growth. These findings provide evidences that ABTL0812 may be an effective therapeutic strategy for targeting cancer. Citation Format: Tatiana Erazo, Mariana Gomez-Ferreria, Jose Alfon, Mar Lorente, Maria Salazar, Anna Lopez, Marc Cortal, Pau Munoz-Guardiola, Pedro Gascon, Guillermo Velasco, Carles Domenech, Jose M. Lizcano. ABTL0812, a new antitumor drug that inhibits the axis Akt/mTOR through a novel mechanism of action. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 672. doi:10.1158/1538-7445.AM2015-672