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.