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Ref Type Journal Article
PMID (23390247)
Authors Allen JE, Krigsfeld G, Mayes PA, Patel L, Dicker DT, Patel AS, Dolloff NG, Messaris E, Scata KA, Wang W, Zhou JY, Wu GS, El-Deiry WS
Title Dual inactivation of Akt and ERK by TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction, and potent antitumor effects.
Journal Science translational medicine
Vol 5
Issue 171
Date 2013 Feb 6
Abstract Text Recombinant tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is an antitumor protein that is in clinical trials as a potential anticancer therapy but suffers from drug properties that may limit efficacy such as short serum half-life, stability, cost, and biodistribution, particularly with respect to the brain. To overcome such limitations, we identified TRAIL-inducing compound 10 (TIC10), a potent, orally active, and stable small molecule that transcriptionally induces TRAIL in a p53-independent manner and crosses the blood-brain barrier. TIC10 induces a sustained up-regulation of TRAIL in tumors and normal cells that may contribute to the demonstrable antitumor activity of TIC10. TIC10 inactivates kinases Akt and extracellular signal-regulated kinase (ERK), leading to the translocation of Foxo3a into the nucleus, where it binds to the TRAIL promoter to up-regulate gene transcription. TIC10 is an efficacious antitumor therapeutic agent that acts on tumor cells and their microenvironment to enhance the concentrations of the endogenous tumor suppressor TRAIL.


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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Nivolumab + ONC201 Nivolumab ONC201 0 1
ONC201 ONC201 13 17
Drug Name Trade Name Synonyms Drug Classes Drug Description
ONC201 TIC-10|TIC10 Akt Inhibitor (Pan) 19 ERK Inhibitor (pan) 15 ONC201 (TIC-10) binds to the G-protein coupled receptor, DRD2, leading to inactivation of AKT and ERK, which relocates Foxo3a to the nucleus and then leads to tumor cell apoptosis mediated by (TNF)-related apoptosis-inducing ligand (TRAIL) signaling (PMID: 23390247) and targets the mitochondrial protease, ClpP (PMID: 31021596, PMID: 31702782, PMID: 31456142).
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
AKT1 amp Advanced Solid Tumor predicted - sensitive ONC201 Preclinical - Cell line xenograft Actionable In a preclinical study, ONC201 (TIC-10) inhibited Akt activation and induced apoptosis and tumor regression in a variety of cell line xenograft models (PMID: 23390247). 23390247
Unknown unknown Advanced Solid Tumor not applicable ONC201 Preclinical - Cell line xenograft Actionable In a preclinical study, ONC-201 (TIC-10) induced apoptosis and tumor regression in a variety of cell line xenograft models, including colon, breast, and brain cancer (PMID: 23390247). 23390247