title: The New Antitumor Drug ABTL0812 Inhibits the Akt/mTORC1 Axis by Upregulating Tribbles-3 Pseudokinase.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Erazo
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universidad Complutense, Madrid, Spain. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Mar
authors.initials: M
authors.lastname: Lorente
authors.affiliation: Area of Molecular and Translational Oncology, IDIBAPS, Fundació Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: López-Plana
authors.affiliation: Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: Pau
authors.initials: P
authors.lastname: Muñoz-Guardiola
authors.affiliation: Area of Molecular and Translational Oncology, IDIBAPS, Fundació Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Patricia
authors.initials: P
authors.lastname: Fernández-Nogueira
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: José A
authors.initials: JA
authors.lastname: García-Martínez
authors.affiliation: Area of Molecular and Translational Oncology, IDIBAPS, Fundació Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Paloma
authors.initials: P
authors.lastname: Bragado
authors.affiliation: Area of Molecular and Translational Oncology, IDIBAPS, Fundació Clínic, Universitat de Barcelona, Barcelona, Spain.
authors.forename: Gemma
authors.initials: G
authors.lastname: Fuster
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universidad Complutense, Madrid, Spain.
authors.forename: María
authors.initials: M
authors.lastname: Salazar
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: Jordi
authors.initials: J
authors.lastname: Espadaler
authors.affiliation: Pathology Department, Hospital Universitari Vall d'Hebron, Barcelona, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Hernández-Losa
authors.affiliation: Institut de Neurociències and Department of Biochemistry and Molecular Biology, Universitat Autònoma de Barcelona, Barcelona, Spain.
authors.forename: Jose Ramon
authors.initials: JR
authors.lastname: Bayascas
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: Marc
authors.initials: M
authors.lastname: Cortal
authors.affiliation: Medical Oncology Department, Novel Therapeutics Unit, Hospital Clínic Barcelona. Barcelona, Catalonia, Spain.
authors.forename: Laura
authors.initials: L
authors.lastname: Vidal
authors.affiliation: Area of Molecular and Translational Oncology, IDIBAPS, Fundació Clínic, Universitat de Barcelona, Barcelona, Spain. Medical Oncology Department, Novel Therapeutics Unit, Hospital Clínic Barcelona. Barcelona, Catalonia, Spain.
authors.forename: Pedro
authors.initials: P
authors.lastname: Gascón
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: Mariana
authors.initials: M
authors.lastname: Gómez-Ferreria
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: José
authors.initials: J
authors.lastname: Alfón
authors.affiliation: Department of Biochemistry and Molecular Biology, Faculty of Biology, Universidad Complutense, Madrid, Spain. Instituto de Investigación Sanitaria del Hospital Clínico San Carlos (IdISSC), Madrid, Spain.
authors.forename: Guillermo
authors.initials: G
authors.lastname: Velasco
authors.affiliation: Ability Pharmaceuticals, SL, Edifici Eureka, Campus UAB, Bellaterra, Barcelona, Catalonia, Spain.
authors.forename: Carles
authors.initials: C
authors.lastname: Domènech
authors.affiliation: Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain. josemiguel.lizcano@uab.es.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Lizcano
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D018797:Cell Cycle Proteins / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1 / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D015854:Up-Regulation / Q000187:drug effects*
chemical_list: D000970:Antineoplastic Agents; D018797:Cell Cycle Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt