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

Abstract

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 micro-environment to enhance the concentrations of the endogenous tumor suppressor TRAIL.

ONC201 induces cell death in pediatric non-Hodgkin's lymphoma cells

“…22 In agreement with the prior findings, an increase in surface DR5 expression in response to ONC201 was noted in a dose-dependent manner (Fig. S1A, B).…”

“…The significant levels of reduction in cell viability and induction of apoptosis were observed at doses that are achievable in mice 22 and in other species in GLP toxicology studies. The fact that ONC201 was effective in both B-cell and T-cell NHL cell lines is in accordance with its broad-spectrum activity that bodes well for its scalability into several indications in the clinic, including pediatric lymphoma.…”

“…The GI50 among this panel ranged from 1.3 to 5.1 mM, which is comparable to reported activity of ONC201 in other tumor types. 22 To further understand the observed activity of ONC201, we performed sub-G1 analysis by flow cytometry that revealed significant levels of apoptosis at 72 hours post-treatment (Fig. 2A).…”

“…5 The power of the immune system in general and TRAIL pathway in particular in cancer suppression motivated our effort to identify small molecules that harness the therapeutic potential of the endogenous death receptor pathway without the limitations of exogenous protein mimetics. 22 Small molecule screening led to the identification of ONC201, a small molecule with a unique pharmacophore that induces TRAIL in a p53-independent manner as well as its proapoptotic receptor DR5, leading to the coordinate activation of apoptosis in tumor cells while sparing normal cells. Mechanistic studies revealed a late-stage inactivation of Akt and ERK that activates Foxo3a, which transcriptionally regulates the TRAIL gene.…”

“…The preclinical efficacy of ONC201 has been reported in a wide range of tumor types as a monoagent and in combination with approved therapies, 22,23 including extension of survival in a Eu-myc transgenic model of lymphoma. A unique feature of ONC201 is the coupling of its strong efficacy and benign safety features, which is particularly important in pediatric cancer patients where genotoxicity is germane and accompanies many of its standard-of-care therapies.…”