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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. | ||||||||||||
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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. |
Molecular Profile | Treatment Approach |
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Gene Name | Source | Synonyms | Protein Domains | Gene Description | Gene Role |
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Therapy Name | Drugs | Efficacy Evidence | Clinical Trials |
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Nivolumab + ONC201 | Nivolumab ONC201 | 0 | 1 |
ONC201 | ONC201 | 0 | 24 |
Drug Name | Trade Name | Synonyms | Drug Classes | Drug Description |
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ONC201 | TIC-10|TIC10 | Akt Inhibitor (Pan) 21 ERK Inhibitor (pan) 21 | 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 |
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Molecular Profile | Indication/Tumor Type | Response Type | Therapy Name | Approval Status | Evidence Type | Efficacy Evidence | References |
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