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

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.

• Authors: Jo Ishizawa, Kensuke Kojima, Dhruv Chachad, Peter Ruvolo, Vivian Ruvolo, Rodrigo O Jacamo, Gautam Borthakur, Hong Mu, Zhihong Zeng, Yoko Tabe, Joshua E Allen, Zhiqiang Wang, Wencai Ma, Hans C Lee, Robert Orlowski, Dos D Sarbassov, Philip L Lorenzi, Xuelin Huang, Sattva S Neelapu, Timothy McDonnell, Roberto N Miranda, Michael Wang, Hagop Kantarjian, Marina Konopleva, R Eric Davis, Michael Andreeff
• Journal: Science signaling (Sci Signal) Vol. 9 Issue 415 Pg. ra17 (Feb 16 2016) ISSN: 1937-9145 [Electronic] United States
• PMID: 26884599 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2016, American Association for the Advancement of Science.

Chemical References

• Atf4 protein, mouse
• Heterocyclic Compounds, 4 or More Rings
• Imidazoles
• Pyridines
• Pyrimidines
• Activating Transcription Factor 4
• TIC10 compound

Topics

• Activating Transcription Factor 4 (metabolism)
• Animals
• Apoptosis (drug effects)
• Cell Line, Tumor
• DNA Damage
• Hematologic Neoplasms (drug therapy, metabolism, pathology)
• Heterocyclic Compounds, 4 or More Rings (pharmacology)
• Imidazoles
• Leukemia, Myeloid, Acute (drug therapy, metabolism, pathology)
• Lymphoma, Mantle-Cell (drug therapy, metabolism, pathology)
• Mice
• Pyridines
• Pyrimidines