title: ONC201 kills solid tumor cells by triggering an integrated stress response dependent on ATF4 activation by specific eIF2α kinases.
abstract: ONC201 (also called TIC10) is a small molecule that inactivates the cell proliferation- and cell survival-promoting kinases Akt and ERK and induces cell death through the proapoptotic protein TRAIL. ONC201 is currently in early-phase clinical testing for various malignancies. We found through gene expression and protein analyses that ONC201 triggered an increase in TRAIL abundance and cell death through an integrated stress response (ISR) involving the transcription factor ATF4, the transactivator CHOP, and the TRAIL receptor DR5. ATF4 was not activated in ONC201-resistant cancer cells, and in ONC201-sensitive cells, knockdown of ATF4 or CHOP partially abrogated ONC201-induced cytotoxicity and diminished the ONC201-stimulated increase in DR5 abundance. The activation of ATF4 in response to ONC201 required the kinases HRI and PKR, which phosphorylate and activate the translation initiation factor eIF2α. ONC201 rapidly triggered cell cycle arrest, which was associated with decreased abundance of cyclin D1, decreased activity of the kinase complex mTORC1, and dephosphorylation of the retinoblastoma (Rb) protein. The abundance of X-linked inhibitor of apoptosis protein (XIAP) negatively correlated with the extent of apoptosis in response to ONC201. These effects of ONC201 were independent of whether cancer cells had normal or mutant p53. Thus, ONC201 induces cell death through the coordinated induction of TRAIL by an ISR pathway.
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: C Leah B
authors.initials: CL
authors.lastname: Kline
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA.
authors.forename: A Pieter J
authors.initials: AP
authors.lastname: Van den Heuvel
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. Oncoceutics Inc., Hummelstown, PA 17036, USA.
authors.forename: Joshua E
authors.initials: JE
authors.lastname: Allen
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: Varun V
authors.initials: VV
authors.lastname: Prabhu
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA.
authors.forename: David T
authors.initials: DT
authors.lastname: Dicker
authors.affiliation: Hematology/Oncology Division and Penn State Hershey Cancer Institute, Penn State College of Medicine, Hershey, PA 17033, USA. Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Department of Hematology/Oncology and Molecular Therapeutics Program, Fox Chase Cancer Center, Philadelphia, PA 19111, USA. wafik.eldeiry@fccc.edu.
authors.forename: Wafik S
authors.initials: WS
authors.lastname: El-Deiry
mesh_terms: D051701:Activating Transcription Factor 4 / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D045744:Cell Line, Tumor; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology*; D006801:Humans; D007093:Imidazoles; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D009374:Neoplasms, Experimental / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011725:Pyridines; D011743:Pyrimidines; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*; D023041:Xenograft Model Antitumor Assays; D019892:eIF-2 Kinase / Q000235:genetics / Q000378:metabolism*
chemical_list: C497109:ATF4 protein, human; D006576:Heterocyclic Compounds, 4 or More Rings; D007093:Imidazoles; D011725:Pyridines; D011743:Pyrimidines; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D051701:Activating Transcription Factor 4; C585684:TIC10 compound; D019892:eIF-2 Kinase