Person:
Bragado Domingo, Paloma

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First Name
Paloma
Last Name
Bragado Domingo
URI
https://hdl.handle.net/20.500.14352/77645
Affiliation
Universidad Complutense de Madrid
Faculty / Institute
Farmacia
Department
Bioquímica y Biología Molecular
Area
Bioquímica y Biología Molecular
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Author: Gemma Fuster × End date: 2021 × Item Type: Publication × Has files: true × Subject: 577.1 × Subject: 612.015 ×

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    The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
    (Clinical Cancer Research, 2016) Bragado Domingo, Paloma; Lorente Pérez, María Del Mar; Salazar Roa, María; Velasco Díez, Guillermo; Tatiana Erazo; Anna Lopez-Plana; Pau Munoz-Guardiola; Patricia Fernandez-Nogueira; Jose A. García-Martínez; Gemma Fuster; Jordi Espadaler; Javier Hernandez-Losa; Jose Ramon Bayascas; Marc Cortal; Laura Vidal; Pedro Gascon; Mariana Gomez-Ferreria; Jose Alfon; Carles Domenech; Jose M. Lizcano; Jose M. Lizcano
    Purpose: ABTL0812 is a novel first-in-class, small molecule which showed antiproliferative effect on tumor cells in phenotypic assays. Here we describe the mechanism of action of this antitumor drug, which is currently in clinical development. Experimental Design: We investigated the effect of ABTL0812 on cancer cell death, proliferation, and modulation of intracellular signaling pathways, using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts. To identify cellular targets, we performed in silico high-throughput screening comparing ABTL0812 chemical structure against ChEMBL15 database. Results: ABTL0812 inhibited Akt/mTORC1 axis, resulting in impaired cancer cell proliferation and autophagy-mediated cell death. In silico screening led us to identify PPARs, PPARα and PPARγ as the cellular targets of ABTL0812. We showed that ABTL0812 activates both PPAR receptors, resulting in upregulation of Tribbles-3 pseudokinase (TRIB3) gene expression. Upregulated TRIB3 binds cellular Akt, preventing its activation by upstream kinases, resulting in Akt inhibition and suppression of the Akt/mTORC1 axis. Pharmacologic inhibition of PPARα/γ or TRIB3 silencing prevented ABTL0812-induced cell death. ABTL0812 treatment induced Akt inhibition in cancer cells, tumor xenografts, and peripheral blood mononuclear cells from patients enrolled in phase I/Ib first-in-human clinical trial. Conclusions: ABTL0812 has a unique and novel mechanism of action, that defines a new and drugable cellular route that links PPARs to Akt/mTORC1 axis, where TRIB3 pseudokinase plays a central role. Activation of this route (PPARα/γ-TRIB3-Akt-mTORC1) leads to autophagy-mediated cancer cell death. Given the low toxicity and high tolerability of ABTL0812, our results support further development of ABTL0812 as a promising anticancer therapy.