ONC201: Stressing tumors to death

Abstract

The small molecule ONC201 was identified in a screen for compounds that would induce expression of the gene encoding tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in tumors and thus cause an autocrine- or paracrine-induced death in tumor cells. Two Research Articles in this issue of Science Signaling by Ishizawa et al. and Kline et al. describe how ONC201 can also trigger cytotoxicity by inducing a stress response. The mechanisms of the stress response induced differ between hematological malignancies and solid tumors, highlighting the complexity of ONC201-induced toxicity and raising intriguing issues of tissue-specific pathways activated by the drug.

Fig. 1.. Structure and mechanism of action of ONC201.

ONC201 induces apoptosis through TRAIL-dependent and TRAIL-independent pathways. In the TRAIL-dependent pathway, ONC201 inhibits AKT and MEK, resulting in the dephosphorylation and nuclear translocation of FOXO3a, which increases transcription of the gene encoding TRAIL. The cells then die by activation of the TRAIL DRs. In the TRAIL-independent pathway, ONC201 induces a stress response by an unknown mechanism. Although the mechanisms of the stress response that are activated appear to be different between solid tumors and hematological malignancies, ATF4 appears to be a common player in these tumor types.