ArticleCancer research2015
Genetic and Pharmacological Screens Converge in Identifying FLIP, BCL2, and IAP Proteins as Key Regulators of Sensitivity to the TRAIL-Inducing Anticancer Agent ONC201/TIC10.
Article in Cancer research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT03034200 (Phase 2 Study of ONC201 in Neuroendocrine Tumors), which is not on this map. Cited by 35 papers, 1 of them a synthesis that pooled it.
What it found
Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.
The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.
The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
Phase 2 Study of ONC201 in Neuroendocrine Tumors
Who cites it
35 citing papers in PubMed, 1 synthesis or guideline pooled it, 45 citations in OpenAlex.
- Mechanisms of imipridones in targeting mitochondrial metabolism in cancer cells.Neuro-oncology · 2021Pooled it
- Biological activity of weekly ONC201 in adult recurrent glioblastoma patients.Neuro-oncology · 2020Trial
- The mitochondrial protease ClpP is a druggable target that controls VSMC phenotype by a SIRT1-dependent mechanism.Redox biology · 2024Article
- Targeting Mitochondria with ClpP Agonists as a Novel Therapeutic Opportunity in Breast Cancer.Cancers · 2023Review
- Therapeutic targeting of TRAIL death receptors.Biochemical Society transactions · 2023Review
- Biological and pharmacological roles of mMolecular cancer · 2022Review
- ONC201-Induced Mitochondrial Dysfunction, Senescence-like Phenotype, and Sensitization of Cultured BT474 Human Breast Cancer Cells to TRAIL.International journal of molecular sciences · 2022Article
- Article
- Small-Molecule Natural Product Physachenolide C Potentiates Immunotherapy Efficacy by Targeting BET Proteins.Cancer research · 2021Article
- Microarray analysis reveals ONC201 mediated differential mechanisms of CHOP gene regulation in metastatic and nonmetastatic colorectal cancer cells.Scientific reports · 2021Article
- Paediatric Gliomas: BRAF and Histone H3 as Biomarkers, Therapy and Perspective of Liquid Biopsies.Cancers · 2021Review
- Article
- ONC201 and imipridones: Anti-cancer compounds with clinical efficacy.Neoplasia (New York, N.Y.) · 2020Review
- TRAIL receptor agonists convert the response of breast cancer cells to ONC201 from anti-proliferative to apoptotic.Oncotarget · 2020Article
- Genomically informed small-molecule drugs overcome resistance to a sustained-release formulation of an engineered death receptor agonist in patient-derived tumor models.Science advances · 2019Article
- Novel Apoptosis-Inducing Agents for the Treatment of Cancer, a New Arsenal in the Toolbox.Cancers · 2019Review
- Development of Novel Anticancer Agents with a Scaffold of Tetrahydropyrido[4,3-ACS medicinal chemistry letters · 2019Article
- Metabolic Reprogramming by Dual AKT/ERK Inhibition through Imipridones Elicits Unique Vulnerabilities in Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Combined HDAC and Bromodomain Protein Inhibition Reprograms Tumor Cell Metabolism and Elicits Synthetic Lethality in Glioblastoma.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Dose intensification of TRAIL-inducing ONC201 inhibits metastasis and promotes intratumoral NK cell recruitment.The Journal of clinical investigation · 2018Article
Corrections and comments
PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.
Authors and funding
9 authors at 1 institution in 1 country.
Funding
Abstract
ONC201/TIC10 is a small-molecule inducer of the TRAIL gene under current investigation as a novel anticancer agent. In this study, we identify critical molecular determinants of ONC201 sensitivity offering potential utility as pharmacodynamic or predictive response markers. By screening a library of kinase siRNAs in combination with a subcytotoxic dose of ONC201, we identified several kinases that ablated tumor cell sensitivity, including the MAPK pathway-inducer KSR1. Unexpectedly, KSR1 silencing did not affect MAPK signaling in the presence or absence of ONC201, but instead reduced expression of the antiapoptotic proteins FLIP, Mcl-1, Bcl-2, cIAP1, cIAP2, and survivin. In parallel to this work, we also conducted a synergy screen in which ONC201 was combined with approved small-molecule anticancer drugs. In multiple cancer cell populations, ONC201 synergized with diverse drug classes, including the multikinase inhibitor sorafenib. Notably, combining ONC201 and sorafenib led to synergistic induction of TRAIL and its receptor DR5 along with a potent induction of cell death. In a mouse xenograft model of hepatocellular carcinoma, we demonstrated that ONC201 and sorafenib cooperatively and safely triggered tumor regressions. Overall, our results established a set of determinants for ONC201 sensitivity that may predict therapeutic response, particularly in settings of sorafenib cotreatment to enhance anticancer responses.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.