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Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule- Dependent Manner Matt L

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Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule- Dependent Manner Matt L Published OnlineFirst February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3511 Translational Cancer Mechanisms and Therapy Clinical Cancer Research Trabectedin Inhibits EWS-FLI1 and Evicts SWI/SNF from Chromatin in a Schedule- dependent Manner Matt L. Harlow1, Maggie H. Chasse2, Elissa A. Boguslawski2, Katie M. Sorensen2, Jenna M. Gedminas2,3,4, Susan M. Kitchen-Goosen2, Scott B. Rothbart2, Cenny Taslim5, Stephen L. Lessnick5,6, Anderson S. Peck2, Zachary B. Madaj2, Megan J. Bowman2,and Patrick J. Grohar2,3,4 Abstract Purpose: The successful clinical translation of compounds Results: Trabectedin evicts the SWI/SNF chromatin- that target specific oncogenic transcription factors will require remodeling complex from chromatin and redistributes an understanding of the mechanism of target suppression to EWS-FLI1 in the nucleus leading to a marked increase optimize the dose and schedule of administration. We have in H3K27me3 and H3K9me3 at EWS-FLI1 target genes. previously shown trabectedin reverses the gene signature of These effects only occur at high concentrations of trabec- the EWS-FLI1 transcription factor. In this report, we establish tedin leading to suppression of EWS-FLI1 target genes the mechanism of suppression and use it to justify the reeval- and a loss of cell viability. In vivo, low-dose irinotecan uation of this drug in the clinic in patients with Ewing sarcoma. is required to improve the magnitude, penetrance, and Experimental Design: We demonstrate a novel epigenetic duration of target suppression in the three-dimensional mechanism of trabectedin using biochemical fractionation architecture of the tumor leading to differentiation of and chromatin immunoprecipitation sequencing. We link the Ewing sarcoma xenograft into benign mesenchymal the effect to drug schedule and EWS-FLI1 downstream target tissue. expression using confocal microscopy, qPCR, Western Conclusions: These data provide the justification to eval- blot analysis, and cell viability assays. Finally, we quantitate uate trabectedin in the clinic on a short infusion schedule in target suppression within the three-dimensional architec- combination with low-dose irinotecan with 18F-FLT PET ture of the tumor in vivo using 18F-FLT imaging. imaging in patients with Ewing sarcoma. Introduction tional druggable domain and most transcription factors interact with complex networks of proteins. Nevertheless, compounds Oncogenic transcription factors are dominant oncogenes for that have successfully targeted specific transcription, such as a large number of leukemias and solid tumors in both the ATRA and arsenic trioxide in acute promyelocytic (APL), are pediatric and adult populations (1–3). These proteins are effective in the clinic (4–6). challenging drug targets because the active site lacks a tradi- Ewing sarcoma is a bone and soft-tissue sarcoma that is absolutely dependent on the EWS-FLI1 transcription factor for 1Department of Cancer Biology, Vanderbilt University, Nashville, Tennessee. cell survival (7). This fusion transcription factor, formed by the 2Van Andel Research Institute, Grand Rapids, Michigan. 3Department of Pedi- t(11;22)(q24;12) chromosomal translocation, both drives 4 atrics, Michigan State University, East Lansing, Michigan. Division of Pediatric proliferation and blocks differentiation (8, 9). EWS-FLI1 acts Hematology/Oncology, Helen DeVos Children's Hospital, Grand Rapids, Michi- 5 as a pioneer transcription factor and binds to repetitive regions gan. Center for Childhood Cancer and Blood Diseases, Nationwide Children's – Hospital Research Institute, Columbus, Ohio. 6Division of Pediatric Hematology/ of the genome called GGAA microsatellites (10 13). Once Oncology/BMT, The Ohio State University College of Medicine, Columbus, Ohio. bound, the protein exhibits phase-transition properties to establish these microsatellites as enhancers to drive gene Note: Supplementary data for this article are available at Clinical Cancer Research Online (http://clincancerres.aacrjournals.org/). expression (14). This requires a complex network of protein interactions and relies heavily on the ATP-dependent chroma- M.L. Harlow and M.H. Chasse contributed equally to this article. tin-remodeling complex, SWI/SNF to maintain chromatin in Current address for M.L. Harlow: Dana-Farber Cancer Institute, Boston, Massa- an open state (14, 15). Therefore, it is likely that reversal of chusetts; current address for A.S. Peck, Bamf Health, Grand Rapids, Michigan; EWS-FLI1activitywouldleadtowidespreadchangesinchro- and current address for M.J. Bowman, Ball Horticultural Company, West Chi- cago, Illinois. matin structure and restore the differentiation program. How- ever, it is not clear whether the effective targeting of EWS-FLI1 Corresponding Author: Patrick J. Grohar, Van Andel Research Institute, 333 requires a blockade of SWI/SNF activity or whether the pioneer Bostwick Ave NE, Grand Rapids, MI 49503. Phone: 616-234-5000; Fax: 616-234- 5309; E-mail: [email protected] transcription factor activity of EWS-FLI1 is reversible genome- wide. Clin Cancer Res 2019;25:3417–29 We have previously shown that the natural product trabectedin doi: 10.1158/1078-0432.CCR-18-3511 interferes with the activity of the EWS-FLI1 transcription fac- Ó2019 American Association for Cancer Research. tor (16). We showed that trabectedin reverses expression of the www.aacrjournals.org 3417 Downloaded from clincancerres.aacrjournals.org on September 30, 2021. © 2019 American Association for Cancer Research. Published OnlineFirst February 5, 2019; DOI: 10.1158/1078-0432.CCR-18-3511 Harlow et al. Translational Relevance Materials and Methods Cell culture This article provides the basis for a clinical trial to evaluate TC32, A673 cells were obtained from Dr. Lee Helman and trabectedin in combination with low-dose irinotecan as an TC252, SK-N-MC, EW8 from Dr. Tim Triche (both at Children's EWS-FLI1–targeted therapy. The clinical suppression of EWS- Hospital of Los Angeles, Los Angeles, CA). Cell identity was FLI1 has not been achieved despite a known dependence on confirmed by short tandem repeat profiling (DDC Medical; last this target for more than 20 years. In addition, trabectedin has test October 24, 2018). They were cultured at 37C pathogen free failed in the disease in a phase II study. These data provide an with 5% CO in RPMI-1640 (Gibco) with 10% FBS (Gemini Bio- explanation for the failed phase II, a schedule change that will 2 Products), 2 mmol/L L-glutamine, and 100 U/mL and 100 mg/mL improve the therapeutic suppression of EWS-FLI1 and evi- penicillin and streptomycin (Gibco). dence that low-dose irinotecan improves the magnitude, pen- etrance, and duration of EWS-FLI1 suppression in vivo.We demonstrate the utility of 18F-FLT to serve as a biomarker of Western blotting EWS-FLI1 suppression in patients. In addition, we establish 1.5 million cells (TC32, A673) or 3 million cells (TC252, a novel mechanism of trabectedin as an inhibitor of the EW8, SK-N-MC) were incubated with drug, washed in PBS, and SWI/SNF chromatin-remodeling complex that is mutated in lysed in 4% lithium dodecyl sulfate (LDS) buffer. Thirty micro- – approximately 25% of all human cancers. grams of total protein were resolved on a NuPage 4 12% Bis- Tris gradient gel (Invitrogen) in 1Â NuPage MOPS SDS Run- ning Buffer (Invitrogen) after diluting detergent and quantitat- ing by bicinchoninic acid (BCA) assay (Pierce, Thermo Scien- tific). The protein was transferred overnight to nitrocellulose at EWS-FLI1 gene signature. In addition, we cloned EWS-FLI1 into 20 V in 1Â Tris-Glycine-SDS Buffer (Bio-Rad) with 20% meth- another cellular context, induced an EWS-FLI1–driven promot- anol. The membranes were blocked in 5% milk in TBS-T, and er luciferase construct, and then rescued this induction with probed with WRN, NR0B1, GAPDH (Abcam), or EZH2 (Cell trabectedin (16). These findings were consistent with early Signaling Technology) antibodies. preclinical and clinical experience with the drug that suggested a heightened sensitivity of Ewing sarcoma to trabecte- din (17, 18). Most notably, a patient with treatment-refractory Quantitative RT-PCR Ewing sarcoma achieved a durable complete response with RNA was collected using the RNeasy Kit (Qiagen), immediately single-agent trabectedin treatment in the phase I study. In reverse-transcribed using a High-Capacity Reverse Transcriptase Kit (Life Technologies) at 25C for 10 minutes, 37C for 120 contrast, the phase II study in Ewing sarcoma was negative and only 1 of 10 patients responded to the drug (19). However, minutes, and 85 C for 10 minutes. The products were quantitated the drug was administered on a different schedule in the using qPCR, SYBR green (Bio-Rad), and the following program: 95C for 10 minutes, 95C for 15 seconds, 55C for 15 seconds, negative phase II study. Therefore, it is possible that a detailed understanding of the mechanism of EWS-FLI1 suppression by and 72 C for 1 minute, for 40 cycles. Expression was determined trabectedin would allow us to optimize the schedule of admin- from three independent experiments relative to GAPDH and DD istration and achieve the therapeutic suppression of EWS-FLI1 solvent control using standard Ct methods. in the clinic. Like many natural products, trabectedin has a complicated Luciferase assays mechanism of action (20, 21). The compound is known to Stable cell lines containing an EWS-FLI1–driven NR0B1 lucif- generate DNA damage and poison various repair pathways, block erase or constitutively active CMV control (25) were incubated
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