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

Tatiana Erazo1, Mar Lorente2, Anna López-Plana3

  • 1Protein Kinases and Signal Transduction Laboratory, Institut de Neurociències and Departament de Bioquímica i Biologia Molecular, Universitat Autònoma de Barcelona, Bellaterra, Barcelona, Spain.

Clinical Cancer Research : an Official Journal of the American Association for Cancer Research
|December 17, 2015
PubMed
Abstract

Insights

ABTL0812, a novel small molecule, inhibits cancer cell proliferation and induces autophagy-mediated cell death by targeting the PPARs-TRIB3-Akt/mTORC1 pathway. This promising anticancer therapy demonstrates low toxicity and high tolerability in clinical trials.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • ABTL0812 is a novel small molecule with demonstrated antiproliferative effects on tumor cells.
  • Understanding its mechanism of action is crucial for its clinical development as an anticancer therapy.

Purpose of the Study:

  • To elucidate the mechanism of action of ABTL0812.
  • To investigate its effects on cancer cell death, proliferation, and signaling pathways.

Main Methods:

  • Phenotypic assays using human lung (A549) and pancreatic (MiaPaCa-2) cancer cells and tumor xenografts.
  • In silico high-throughput screening against the ChEMBL15 database to identify cellular targets.
  • Analysis of intracellular signaling pathways, including Akt/mTORC1 and PPARs.

Main Results:

  • ABTL0812 inhibits the Akt/mTORC1 axis, leading to impaired cancer cell proliferation and autophagy-mediated cell death.
  • In silico screening identified peroxisome proliferator-activated receptors (PPARs), specifically PPARα and PPARγ, as cellular targets.
  • ABTL0812 activates PPARα/γ, upregulating Tribbles-3 pseudokinase (TRIB3) expression, which inhibits Akt activation and suppresses the Akt/mTORC1 axis.
  • Pharmacologic inhibition of PPARα/γ or TRIB3 silencing abolished ABTL0812-induced cell death.
  • Akt inhibition was observed in cancer cells, xenografts, and patient-derived peripheral blood mononuclear cells.

Conclusions:

  • ABTL0812 possesses a novel mechanism of action involving the PPARs-TRIB3-Akt/mTORC1 pathway, leading to autophagy-mediated cancer cell death.
  • This pathway represents a new, druggable target for cancer therapy.
  • The low toxicity and high tolerability of ABTL0812 support its further development as a promising anticancer agent.

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