title: 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.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Jo
authors.initials: J
authors.lastname: Ishizawa
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Division of Hematology, Respiratory Medicine and Oncology, Department of Medicine, Saga University, Saga 840-8502, Japan.
authors.forename: Kensuke
authors.initials: K
authors.lastname: Kojima
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dhruv
authors.initials: D
authors.lastname: Chachad
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Ruvolo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Vivian
authors.initials: V
authors.lastname: Ruvolo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Rodrigo O
authors.initials: RO
authors.lastname: Jacamo
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Gautam
authors.initials: G
authors.lastname: Borthakur
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hong
authors.initials: H
authors.lastname: Mu
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhihong
authors.initials: Z
authors.lastname: Zeng
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. Department of Clinical Laboratory Medicine, Juntendo University School of Medicine, Tokyo 113-8431, Japan.
authors.forename: Yoko
authors.initials: Y
authors.lastname: Tabe
authors.affiliation: Oncoceutics Inc., Hummelstown, PA 19104, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Zhiqiang
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Wencai
authors.initials: W
authors.lastname: Ma
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hans C
authors.initials: HC
authors.lastname: Lee
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Robert
authors.initials: R
authors.lastname: Orlowski
authors.affiliation: Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Dos D
authors.initials: dos D
authors.lastname: Sarbassov
authors.affiliation: Department of Bioinformatics and Computational Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Philip L
authors.initials: PL
authors.lastname: Lorenzi
authors.affiliation: Department of Biostatistics, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Xuelin
authors.initials: X
authors.lastname: Huang
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Sattva S
authors.initials: SS
authors.lastname: Neelapu
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Timothy
authors.initials: T
authors.lastname: McDonnell
authors.affiliation: Department of Hematopathology, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Roberto N
authors.initials: RN
authors.lastname: Miranda
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Wang
authors.affiliation: Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Hagop
authors.initials: H
authors.lastname: Kantarjian
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: Marina
authors.initials: M
authors.lastname: Konopleva
authors.affiliation: Department of Lymphoma/Myeloma, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mandreef@mdanderson.org redavis1@mdanderson.org.
authors.forename: R Eric
authors.initials: RE
authors.lastname: Davis
authors.affiliation: Section of Molecular Hematology and Therapy, Department of Leukemia, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA. mandreef@mdanderson.org redavis1@mdanderson.org.
authors.forename: Michael
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authors.lastname: Andreeff
mesh_terms: D051701:Activating Transcription Factor 4 / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D004249:DNA Damage; D019337:Hematologic Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D007093:Imidazoles; D015470:Leukemia, Myeloid, Acute / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D020522:Lymphoma, Mantle-Cell / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D051379:Mice; D011725:Pyridines; D011743:Pyrimidines
chemical_list: C081452:Atf4 protein, mouse; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; D051701:Activating Transcription Factor 4; C585684:TIC10 compound