ϟ
 
DOI: 10.1158/1078-0432.ccr-15-1808
OpenAccess: Closed
This work is not Open Acccess. We may still have a PDF, if this is the case there will be a green box below.

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

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,José R. Bayascas,Marc Cortal,Laura Vidal,Pedro Gascón,Mariana Gómez-Ferrería,José Alfón,Guillermo Velasco,Carles Domènech,José M. Lizcano

mTORC1
Protein kinase B
PI3K/AKT/mTOR pathway
2016
Abstract 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. Clin Cancer Res; 22(10); 2508–19. ©2015 AACR.
Loading...
    Cite this:
Generate Citation
Powered by Citationsy*
    The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase” is a paper by 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 José R. Bayascas Marc Cortal Laura Vidal Pedro Gascón Mariana Gómez-Ferrería José Alfón Guillermo Velasco Carles Domènech José M. Lizcano published in 2016. It has an Open Access status of “closed”. You can read and download a PDF Full Text of this paper here.