Identification of TRAIL-inducing compounds highlights small molecule ONC201/TIC10 as a unique anti-cancer agent that activates the TRAIL pathway
Authors: Joshua E Allen
Gen Sheng Wu
David T Dicker
Luv Patel
Patrick A Mayes
Gabriel Krigsfeld
Wafik S El-Deiry
Journal: Molecular Cancer (2015)
Discipline: MOLECULAR BIOLOGY & GENETICS
Keywords: ONC201/TIC10; TRAIL; apoptosis; tumor cells; cell death
Affiliations: Departments of Medicine, Genetics, and Pharmacology, Laboratory of Molecular Oncology and Cell Cycle Regulation, University of Pennsylvania School of Medicine, Philadelphia, 19104, PA, USA. ., Current affiliation: Oncoceutics, Inc., Hummelstown, PA, USA. ., Department of Medical Oncology and Molecular Therapeutics Program, Laboratory of Translational Oncology and Experimental Cancer Therapeutics, Fox Chase Cancer Center, Philadelphia, 19111, PA, USA. ., Department of Pathology, Program in Molecular Biology and Genetics, Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, 48201, USA. .

Abstract:  Background: We previously reported the identification of ONC201/TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in advanced cancers based on its promising safety and antitumor efficacy in several preclinical models. Methods: We performed a high throughput luciferase reporter screen using the NCI Diversity Set II to identify TRAIL-inducing compounds. Results: Small molecule-mediated induction of TRAIL reporter activity was relatively modest and the majority of the hit compounds induced low levels of TRAIL upregulation. Among the candidate TRAIL-inducing compounds, TIC9 and ONC201/TIC10 induced sustained TRAIL upregulation and apoptosis in tumor cells in vitro and in vivo. However, ONC201/TIC10 potentiated tumor cell death while sparing normal cells, unlike TIC9, and lacked genotoxicity in normal fibroblasts. Investigating the effects of TRAIL-inducing compounds on cell signaling pathways revealed that TIC9 and ONC201/TIC10, which are the most potent inducers of cell death, exclusively activate Foxo3a through inactivation of Akt/ERK to upregulate TRAIL and its pro-apoptotic death receptor DR5. Conclusion: These studies reveal the selective activity of ONC201/TIC10 that led to its selection as a lead compound for this novel class of antitumor agents and suggest that ONC201/TIC10 is a unique inducer of the TRAIL pathway through its concomitant regulation of the TRAIL ligand and its death receptor DR5. 

Retracted: No

PubPeer comments:
 Figure 3b includes two images which are unexpectedly similar. *** ![file] , 
 Thank you for bringing this to our attention. We have sent the below note to the journal along with the attached corrected figure (high resolution sent to the journal). Dear Editors: Regarding the below manuscript: Identification of TRAIL-inducing compounds highlights small molecule ONC201 TIC10 as a unique anti-cancer agent that activates the TRAIL pathway We previously reported the identification of ONC201 TIC10, a novel small molecule inducer of the human TRAIL gene that improves efficacy-limiting properties of recombinant TRAIL and is in clinical trials in ad... Authors:Joshua E Allen, Gabriel Krigsfeld, Luv Patel, Patrick A Mayes, David T Dicker, Gen Sheng Wu and Wafik S El-Deiry Citation:Molecular Cancer 2015 14:99 Content type:Research Published on: 1 May 2015 We request that you consider publishing a correction to Figure 4B (Corrected Figure 4B is attached). Please include the following text with the correction:  After publication, the authors were alerted to an error in Figure 4B that shows a duplication of a histological image in two panels in the figure. This image duplication error in Figure 4B was missed by all the authors and reviewers of the paper. The duplicated image has been replaced and the images, as well as their labels, have been accurately arranged in the corrected Figure 4B. We apologize for the oversight and original error. The original error does not impact the description or interpretation of the data stated in the manuscript. The corrected Figure 4B was provided by the first author along with the following explanation: While investigating this figure panel against source data I confirmed that one image was accidentally duplicated, resulting in the omission of another image that is now included in Figure 4B. I also addressed labeling arrangement errors in this panel. The corrected Figure 4B accurately reflects the results of the experiment that I performed.u201d Thank you very much for considering this request. Sincerely, W. El-Deiry on behalf of all the authors.![file] , 
 Figure 3B (not 4B). , 
 #3 Is there any update? ,