The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase

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 ABTL0...

Descripción completa

Detalles Bibliográficos
Autores: Erazo, Tatiana, Lorente, Mar, López Plana, Anna, Muñoz Guardiola, Pau, Fernandez-Nogueira, Patricia, García-Martinez, José A., Bragado Domingo, Paloma, Fuster Orellana, Gemma, Salazar, María, Espadaler, Jordi, Hernández Losa, Javier, Bayascas, Jose R., Cortal, Marc, Vidal, Laura, Gascón, Pere, Gómez Ferreria, Mariana, Alfón, José, Velasco, Guillermo, Domènech, Carles, Lizcano, José Miguel
Tipo de recurso: artículo
Estado:Versión aceptada para publicación
Fecha de publicación:2016
País:España
Institución:Varias* (Consorci de Biblioteques Universitáries de Catalunya, Centre de Serveis Científics i Acadèmics de Catalunya)
Repositorio:Recercat. Dipósit de la Recerca de Catalunya
OAI Identifier:oai:recercat.cat:2445/207600
Acceso en línea:https://hdl.handle.net/2445/207600
Access Level:acceso abierto
Palabra clave:Tumors
Proteïnes
Medicaments antineoplàstics
Cicle cel·lular
Transducció de senyal cel·lular
Apoptosi
Cèl·lules canceroses
Proteins
Antineoplastic agents
Cell cycle
Cellular signal transduction
Apoptosis
Cancer cells
Descripción
Sumario: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.

Similares en LA Referencia