Research ArticlePharmacology

ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases

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Science Signaling  16 Feb 2016:
Vol. 9, Issue 415, pp. ra18
DOI: 10.1126/scisignal.aac4374

Stressing cancer cells to death

The anticancer drug ONC201 triggers cell death in various tumor types. A pair of papers (see also the Focus by Greer and Lipkowitz) show that ONC201 activated cell stress pathways that depended on the activation of the transcription factor ATF4. Kline et al. showed this stress response to ONC201 occurred in cells derived from various types of solid tumors, in which ATF4 activation led to an increase in the abundance of the proapoptotic protein TRAIL and its receptor DR5. Ishizawa et al. demonstrated that in acute myeloid leukemia and mantle cell lymphoma, ONC201 triggered apoptosis and inhibited mTORC1 signaling, a pathway that promotes cell growth and proliferation. The findings reveal more details about ONC201’s mechanism of action, potentially enabling patient stratification and future development to improve its efficacy.

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