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Anti-cancer agent ONC201 activates early ATF4/DR5 upregulation, and cell death associated with XIAP inhibition

ABSTRACT: Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE72865 | GEO | 2016/06/01

SECONDARY ACCESSION(S): PRJNA295215

REPOSITORIES: GEO

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Anti-cancer agent ONC201 activates early ATF4/DR5 upregulation, and cell death associated with XIAP inhibition

Project description:Two experiments were performed with ONC201/TIC10 in human colon cancer cell lines. The first experiment is TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM). The second experiment is RKO cells, with and without acquired resistance to ONC201, treated with with ONC201 (10uM) for 48 hrs. For the first experiment, six samples of HCT116 p53-null cells with TIC10 (10uM) or DMSO treatment. Three replicates each. For the second experiment, six samples of wild-type RKO cells with ONC201 (10uM) or DMSO treatment and the same treatments for RKO cells with acquired resistance to ONC201.

2016-06-01 | E-GEOD-72865 | biostudies-arrayexpress

Effects of ONC201 on mantle cell lymphoma cell lines

Project description:The small molecule ONC201 is toxic in vitro to multiple cell lines and primary tumor samples of mantle cell lymphoma (MCL) and acute myeloid leukemia, even ones with unfavorable genetic features (notably including TP53 inactivation) or acquired resistance to other agents. Because the mechanism of action in these malignant hematologic cells appeared to differ from that in solid tumors, we performed gene expression profiling (GEP) studies on MCL lines treated with ONC201 and other agents with known mechanisms of action. Treatment of JeKo-1 cells with 5 uM ONC201 showed consistent and progressive increases or decreases over time in two sets of genes: upregulated genes, which implicated an ER stress response and mTOR pathway inhibition, and downregulated genes, which implicated reduced proliferation. These implicated effects of ONC201 were validated by confirmatory experiments. Similar GEP changes were observed in ONC201-naive Z138 cells after 24 hr of ONC201 treatment, but were not seen in Z138 cells made ONC201-resistant by chronic exposure. Finally, the GEP effects of ONC201 in JeKo-1 cells were mimicked by the ER stress inducer tunicamycin, but not by the direct MTOR inhibition rapamycin, further confirming an ER stress response and suggesting that inhibition of the mTOR pathway was by an indirect mechanism. For each experiment, cells from a single stock culture of each cell line used were aliquoted into individual culture plate wells, establishing individual replicates, and drugs were added to start the experiment. Treated replicates were harvested after the times of treatment indicated, by pelleting cells, lysing pellets in TriZOL, and freezing TriZOL until RNA isolation. Untreated replicates, serving as controls, were either harvested at the beginning of the experiment or at later times, as specified below.

2016-02-20 | E-GEOD-68091 | biostudies-arrayexpress

Effects of ONC201 on mantle cell lymphoma cell lines

2016-02-20 | GSE68091 | GEO

Patient-derived HK-374 glioblastoma cells treated with radiation and ONC201

Project description:RNASeq results for HK-374 treated with DMSO, radiation, ONC201 or radiation plus ONC201

2020-07-08 | GSE153982 | GEO

Effect of TIC10/ONC201 on glioma cells

Project description:We performed microarray analysis in order to evaluate the effect of ONC201 on gene expression in glioma cells (U87).

2019-09-18 | GSE103963 | GEO

Dual inactivation of Akt and ERK by small molecule TIC10 signals Foxo3a nuclear translocation, TRAIL gene induction and potent anti-tumor effects

Project description:TIC10-induced transcriptional changes at 48hrs in HCT116 p53-null cells (10uM).

2013-03-08 | GSE34194 | GEO

ONC201 in combination with paxalisib for the treatment of H3K27-altered diffuse midline glioma

Project description:Diffuse midline gliomas (DMG), including diffuse intrinsic pontine gliomas (DIPGs), are the most lethal of all childhood cancers. Palliative radiotherapy is the only proven life-prolonging treatment, with patient survival 9-11 months. ONC201 shows preclinical and emerging clinical efficacy in DIPG. Currently, little is known about the mechanisms of sensitivity/resistance of DIPGs to ONC201, or whether recurring genomic features influence response. Using a systems-biological approach, we show ONC201 elicits potent agonism of the mitochondrial protease, CLPP, driving proteolysis of electron transport chain (ETC) and tricarboxylic acid (TCA) cycle proteins. DIPGs harboring TP53-mutations show reduced sensitivity to ONC201. Molecular mechanisms identify metabolic adaptation and resistance to ONC201 regulated by redox-activated PI3K/Akt signaling, counteracted using the brain penetrant PI3K/Akt inhibitor, paxalisib, in both wt-TP53 and TP53-mutant DIPGs. The discoveries described within, coupled with the powerful anti-DIPG/DMG pharmacokinetic and pharmacodynamic properties of ONC201 and paxalisib inform the DIPG/DMG phase II combination clinical trial NCT05009992.

2023-05-25 | PXD036245 | Pride

Effect of ONC201 and its derivatives (ONC206 and ONC212) on glioma cells

Project description:We performed microarray analysis in order to evaluate the effect of ONC201 and its derivatives (ONC206 and ONC212) on gene expression in U87 glioma cells.

2018-09-25 | GSE104273 | GEO

Genome-wide gene expression profile of human DIPG cell lines (ONC201 treatment)

Project description:To study the effect of ONC201 treatment on DIPG-VII, DIPG-IV, and DIPG-XIII cell lines, we treated cell lines and performed RNA-Seq analysis.

2023-12-31 | GSE239939 | GEO

Testing ONC201 to Prevent Colorectal Cancer

Project description:This phase I trial tests the safety, side effects, and best dose of Akt/ERK Inhibitor ONC201 (ONC201) in preventing colorectal cancer in patients with familial adenomatous polyposis (FAP) or a history of multiple polyps. ONC201 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

| 860 | ecrin-mdr-crc

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