Research ArticlePharmacology

ATF4 induction through an atypical integrated stress response to ONC201 triggers p53-independent apoptosis in hematological malignancies

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Science Signaling  16 Feb 2016:
Vol. 9, Issue 415, pp. ra17
DOI: 10.1126/scisignal.aac4380

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) shows that ONC201 activated cell stress pathways that depended on the activation of the transcription factor ATF4. Kline et al. showed that 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 leukemias 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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