RT Journal Article
T1 The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase
A1 Erazo, Tatiana
A1 Lorente Pérez, María Del Mar
A1 Lopez-Plana, Anna
A1 Munoz-Guardiola, Pau
A1 Fernandez-Nogueira, Patricia
A1 García-Martínez, Jose
A1 Bragado Domingo, Paloma
A1 Fuster, Gemma
A1 Salazar Roa, María
A1 Espadaler, Jordi
A1 Hernandez-Losa, Javier
A1 Bayascas, Jose Ramon
A1 Cortal, Marc
A1 Vidal, Laura
A1 Gascon, Pedro
A1 Gomez-Ferreria, Mariana
A1 Alfon, Jose
A1 Velasco Díez, Guillermo
A1 Domenech, Carles
A1 Lizcano, Jose
AB 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.
PB American Association for Cancer Research
SN 1078-0432
YR 2016
FD 2016
LK https://hdl.handle.net/20.500.14352/97280
UL https://hdl.handle.net/20.500.14352/97280
LA eng
NO Tatiana Erazo, Mar Lorente, Anna López-Plana, Pau Muñoz-Guardiola, Patricia Fernández-Nogueira, José A. García-Martínez, Paloma Bragado, Gemma Fuster, María Salazar, Jordi Espadaler, Javier Hernández-Losa, Jose Ramon Bayascas, Marc Cortal, Laura Vidal, Pedro Gascón, Mariana Gómez-Ferreria, José Alfón, Guillermo Velasco, Carles Domènech, Jose M. Lizcano; The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase. Clin Cancer Res 15 May 2016; 22 (10): 2508–2519. https://doi.org/10.1158/1078-0432.CCR-15-1808
NO Fundación Mutua Madrileña
NO Generalitat de Catalunya
NO Ministerio de Economía y Competitividad (España)
NO European Commission
DS Docta Complutense
RD 29 sept 2024