Journal article
Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner
Clinical cancer research, Vol.25(11), pp.3417-3429
06/01/2019
DOI: 10.1158/1078-0432.CCR-18-3511
PMCID: PMC6594545
PMID: 30723142
Abstract
Purpose: The successful clinical translation of compounds that target specific oncogenic transcription factors will require an understanding of the mechanism of target suppression to optimize the dose and schedule of administration. We have previously shown trabectedin reverses the gene signature of the EWS-FLI1 transcription factor. In this report, we establish the mechanism of suppression and use it to justify the reevaluation of this drug in the clinic in patients with Ewing sarcoma.
Experimental Design: We demonstrate a novel epigenetic mechanism of trabectedin using biochemical fractionation and chromatin immunoprecipitation sequencing. We link the effect to drug schedule and EWS-FLI1 downstream target expression using confocal microscopy, qPCR, Western blot analysis, and cell viability assays. Finally, we quantitate target suppression within the three-dimensional architecture of the tumor in vivo using F-18-FLT imaging.
Results: Trabectedin evicts the SWI/SNF chromatin-remodeling complex from chromatin and redistributes EWS-FLI1 in the nucleus leading to a marked increase in H3K27me3 and H3K9me3 at EWS-FLI1 target genes. These effects only occur at high concentrations of trabectedin leading to suppression of EWS-FLI1 target genes and a loss of cell viability. In vivo, low-dose irinotecan is required to improve the magnitude, penetrance, and duration of target suppression in the three-dimensional architecture of the tumor leading to differentiation of the Ewing sarcoma xenograft into benign mesenchymal tissue.
Conclusions: These data provide the justification to evaluate trabectedin in the clinic on a short infusion schedule in combination with low-dose irinotecan with F-18-FLT PET imaging in patients with Ewing sarcoma.
Details
- Title: Subtitle
- Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule-dependent Manner
- Creators
- Matt L. Harlow - Vanderbilt UniversityMaggie H. Chasse - Van Andel InstituteElissa A. Boguslawski - Van Andel InstituteKatie M. Sorensen - Van Andel InstituteJenna M. Gedminas - Michigan State UniversitySusan M. Kitchen-Goosen - Van Andel InstituteScott B. Rothbart - Van Andel InstituteCenny Taslim - Nationwide Children's HospitalStephen L. Lessnick - The Ohio State UniversityAnderson S. Peck - Van Andel InstituteZachary B. Madaj - Van Andel InstituteMegan J. Bowman - Van Andel InstitutePatrick J. Grohar - Michigan State University
- Resource Type
- Journal article
- Publication Details
- Clinical cancer research, Vol.25(11), pp.3417-3429
- DOI
- 10.1158/1078-0432.CCR-18-3511
- PMID
- 30723142
- PMCID
- PMC6594545
- NLM abbreviation
- Clin Cancer Res
- ISSN
- 1078-0432
- eISSN
- 1557-3265
- Publisher
- Amer Assoc Cancer Research
- Number of pages
- 13
- Grant note
- F31CA236300 / NIH/NCI MHC U54CA231641; R01CA183776 / NIH/NCI; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Van Andel Institute R01-CA188314 / NIH; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA F31CA236300 / NATIONAL CANCER INSTITUTE; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Cancer Institute (NCI) Reach Award from Alex's Lemonade Stand Foundation R35GM124736 / NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS) Hyundai Hope on Wheels R35GM124736 / NIH/NIGMS; United States Department of Health & Human Services; National Institutes of Health (NIH) - USA; NIH National Institute of General Medical Sciences (NIGMS)
- Language
- English
- Date published
- 06/01/2019
- Academic Unit
- Stead Family Department of Pediatrics; Hematology/Oncology
- Record Identifier
- 9984354037102771
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