Research ArticlePharmacology

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

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

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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.

Abstract

The clinical challenge posed by p53 abnormalities in hematological malignancies requires therapeutic strategies other than standard genotoxic chemotherapies. ONC201 is a first-in-class small molecule that activates p53-independent apoptosis, has a benign safety profile, and is in early clinical trials. We found that ONC201 caused p53-independent apoptosis and cell cycle arrest in cell lines and in mantle cell lymphoma (MCL) and acute myeloid leukemia (AML) samples from patients; these included samples from patients with genetic abnormalities associated with poor prognosis or cells that had developed resistance to the nongenotoxic agents ibrutinib and bortezomib. Moreover, ONC201 caused apoptosis in stem and progenitor AML cells and abrogated the engraftment of leukemic stem cells in mice while sparing normal bone marrow cells. ONC201 caused changes in gene expression similar to those caused by the unfolded protein response (UPR) and integrated stress responses (ISRs), which increase the translation of the transcription factor ATF4 through an increase in the phosphorylation of the translation initiation factor eIF2α. However, unlike the UPR and ISR, the increase in ATF4 abundance in ONC201-treated hematopoietic cells promoted apoptosis and did not depend on increased phosphorylation of eIF2α. ONC201 also inhibited mammalian target of rapamycin complex 1 (mTORC1) signaling, likely through ATF4-mediated induction of the mTORC1 inhibitor DDIT4. Overexpression of BCL-2 protected against ONC201-induced apoptosis, and the combination of ONC201 and the BCL-2 antagonist ABT-199 synergistically increased apoptosis. Thus, our results suggest that by inducing an atypical ISR and p53-independent apoptosis, ONC201 has clinical potential in hematological malignancies.

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