Research ArticleCancer

Dual Inactivation of Akt and ERK by TIC10 Signals Foxo3a Nuclear Translocation, TRAIL Gene Induction, and Potent Antitumor Effects

Science Translational Medicine  06 Feb 2013:
Vol. 5, Issue 171, pp. 171ra17
DOI: 10.1126/scitranslmed.3004828

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TIC’ing Up the TRAIL

TRAIL is a naturally occurring tumor suppressor: It stimulates cell death pathways in a variety of human cancers and thus has been a popular target for the development of anticancer drugs. Previous TRAIL-targeting strategies include synthesis of the recombinant protein and stimulatory antibodies. All of these agents exhibit some of the typical drawbacks of protein-based therapeutics, such as short half-lives and a need to administer the drugs directly into the bloodstream or even into the tumor. Now, Allen and colleagues have discovered a drug, TIC10, which can stimulate production of TRAIL while avoiding the shortcomings of protein-based therapies.

The authors demonstrated that TIC10 can increase TRAIL and stimulate the death of multiple types of human cancer cells both in culture and in mice. The drug was equally effective when given orally or intravenously and effectively penetrated the blood-brain barrier to target glioblastoma, a difficult-to-treat brain tumor. Whereas recombinant TRAIL displayed a short half-life of ~30 min, TIC10 activity persisted in the mice for days, allowing for once-a-week dosing. Toxicity analysis in mice showed no detectable adverse effects from treatment with TIC10. The authors also showed that TIC10 boosts TRAIL function through inactivation of the Akt and MEK signaling proteins, which results in translocation of the transcription factor Foxo3a into the cell nucleus, where it stimulates TRAIL gene expression.

Before TIC10 can be used to treat patients, the drug will need to be tested in clinical trials to confirm safety and efficacy results from mouse studies. In addition, further work is needed to determine the mechanism by which TIC10 causes the dephosphorylation and resulting inactivation of Akt and MEK. However, the discovery of TIC10 clears a path to versatile TRAIL-based cancer therapies.