EWS-FLI1 confers exquisite sensitivity to NAMPT inhibition in Ewing sarcoma cells
Bibliographic record
Abstract
// Cornelia N. Mutz 1 , Raphaela Schwentner 1 , Dave N.T. Aryee 1, 5 , Eric D.J. Bouchard 2 , Edgard M. Mejia 3 , Grant M. Hatch 4 , Maximilian O. Kauer 1 , Anna M. Katschnig 1 , Jozef Ban 1 , Antje Garten 6 , Javier Alonso 7 , Versha Banerji 2 , Heinrich Kovar 1, 5 1 Children’s Cancer Research Institute Vienna, St. Anna Kinderkrebsforschung, Vienna, Austria 2 Department of Biochemistry and Medical Genetics, University of Manitoba, Research Institute in Oncology and Hematology (RIOH), CancerCare Manitoba, Winnipeg, Canada 3 Department of Pharmacology and Therapeutics, Faculty of Health Sciences, University of Manitoba, Winnipeg, Canada 4 Department of Biochemistry and Medical Genetics, Center for Research and Treatment of Atherosclerosis, University of Manitoba, DREAM Children’s Hospital Research Institute of Manitoba, Winnipeg, Canada 5 Department of Pediatrics, Medical University Vienna, Vienna, Austria 6 Center for Pediatric Research Leipzig, Hospital for Children and Adolescents, University of Leipzig, Leipzig, Germany 7 Unidad de Tumores Sólidos Infantiles, Instituto de Investigación de Enfermedades Raras, ISCIII, Ctra, Madrid, Spain Correspondence to: Heinrich Kovar, email: heinrich.kovar@ccri.at Keywords: EWS-FLI1, Ewing sarcoma, NAMPT, NAD, FK866 Received: May 10, 2016 Accepted: January 16, 2017 Published: February 01, 2017 ABSTRACT Ewing sarcoma (EwS) is the second most common bone cancer in children and adolescents with a high metastatic potential. EwS development is driven by a specific chromosomal translocation resulting in the generation of a chimeric EWS-ETS transcription factor, most frequently EWS-FLI1. Nicotinamide adenine dinucleotide (NAD) is a key metabolite of energy metabolism involved in cellular redox reactions, DNA repair, and in the maintenance of genomic stability. This study describes targeting nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD synthesis, by FK866 in EwS cells. Here we report that blocking NAMPT leads to exhaustive NAD depletion in EwS cells, followed by a metabolic collapse and cell death. Using conditional EWS-FLI1 knockdown by doxycycline-inducible shRNA revealed that EWS-FLI1 depletion significantly reduces the sensitivity of EwS cells to NAMPT inhibition. Consistent with this finding, a comparison of 7 EwS cell lines of different genotypes with 5 Non-EwS cell lines and mesenchymal stem cells revealed significantly higher FK866 sensitivity of EWS-ETS positive EwS cells, with IC 50 values mostly below 1nM. Taken together, our data reveal evidence of an important role of the NAMPT-mediated NAD salvage pathway in the energy homeostasis of EwS cells and suggest NAMPT inhibition as a potential new treatment approach for Ewing sarcoma.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one teacher head, not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".