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ResearchIn-Press PreviewCell biologyOncology Open Access | 10.1172/JCI179282

Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas

Yaniv Kazansky,1 Helen S. Mueller,1 Daniel Cameron,1 Phillip Demarest,1 Nadia Zaffaroni,2 Noemi Arrighetti,2 Valentina Zuco,2 Prabhjot S. Mundi,3 Yasumichi Kuwahara,4 Romel Somwar,5 Rui Qu,6 Andrea Califano,3 Elisa de Stanchina,6 Filemon S. Dela Cruz,7 Andrew L. Kung,7 Mrinal M. Gounder,8 and Alex Kentsis1

1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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1Molecular Pharmacology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, United States of America

2Molecular Pharmacology Unit, Department of Experimental Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori di Milano, Milan, Italy

3Department of Systems Biology, Columbia University Irving Medical Center, New York, United States of America

4Department of Biochemistry and Molecular Biology, Kyoto Prefectural University of Medicine, Kyoto, Japan

5Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, United States of America

6Antitumor Assessment Core, Memorial Sloan Kettering Cancer Center, New York, United States of America

7Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, United States of America

8Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, United States of America

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Published August 12, 2025 - More info

J Clin Invest. https://doi.org/10.1172/JCI179282.
Copyright © 2025, Kazansky et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published August 12, 2025 - Version history
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Abstract

Despite the potential of targeted epigenetic therapies, most cancers do not respond to current epigenetic drugs. The Polycomb repressive complex EZH2 inhibitor tazemetostat was recently approved for the treatment of SMARCB1-deficient epithelioid sarcomas, based on the functional antagonism between PRC2 and SMARCB1. Through the analysis of tazemetostat-treated patient tumors, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominated the DNA damage repair kinase ATR as a target for rational EZH2 combination epigenetic therapy. We showed that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of piggyBac transposable element derived 5 (PGBD5). We leveraged this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR, but not CHK1, using the ATR inhibitor elimusertib. Consequently, combined EZH2 and ATR inhibition improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors in vivo. This advances a combination epigenetic therapy based on EZH2-PGBD5 synthetic lethal dependency suitable for immediate translation to clinical trials for patients.

Supplemental material

View Supplementary Table S1: Rank-ordered list of predicted most active proteins in rhabdoid tumor cell lines after metaVIPER analysis for the subset for which there are pharmacological inhibitors (OncoTarget genes). Supplement to Figure 1A.

View Unedited blot and gel images

View Supplementary Table S2: Rank-ordered list of predicted most active proteins in rhabdoid tumor cell lines after metaVIPER analysis for the full metaVIPER gene set. Supplement to Figure 1B.

View Supplementary Table S3: List of IC50s (nM) of inhibitors rank-ordered by response in rhabdoid tumor cell lines from Kuster et al., listed for both the mean of the three rhabdoid tumor cell lines and individually for each cell line. Supplement to Figure 1C.

View Supplementary Table S4: List of PDX models used in this study, with clinical characteristics of the original tumor specimens, followed by a list of mutations found in all PDX models, as determined by targeted MSK-IMPACT sequencing.

Version history
  • Version 1 (August 12, 2025): In-Press Preview
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