Epigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas
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 tumors of patients treated with tazemetostat, we recently defined key principles of their response and resistance to EZH2 epigenetic therapy. Here, using transcriptomic inference from SMARCB1-deficient tumor cells, we nominate 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.
Authors
- Helen S. Mueller (ORCID: https://orcid.org/0000-0001-5813-873X)
- Elisa de Stanchina (ORCID: https://orcid.org/0000-0002-3873-315X)
- Phillip Demarest (ORCID: https://orcid.org/0009-0005-0330-8785)
- Romel Somwar
- Mrinal M. Gounder (ORCID: https://orcid.org/0000-0001-8468-0119)
- Prabhjot Singh Mundi (ORCID: https://orcid.org/0000-0001-9871-4463)
- Andrea Califano (ORCID: https://orcid.org/0000-0003-4742-3679)
- Alex Kentsis (ORCID: https://orcid.org/0000-0002-8063-9191)
- Daniel Cameron (ORCID: https://orcid.org/0000-0002-0951-7116)
- Andrew L. Kung (ORCID: https://orcid.org/0000-0002-9091-488X)
- Filemon S. Dela Cruz (ORCID: https://orcid.org/0000-0002-8356-5191)
- Noemi Arrighetti (ORCID: https://orcid.org/0000-0001-9848-3239)
- Rui Qu (ORCID: https://orcid.org/0009-0009-1185-9076)
- Yasumichi Kuwahara (ORCID: https://orcid.org/0000-0002-0139-8503)
- Yaniv Kazansky (ORCID: https://orcid.org/0000-0003-3467-5703)
- Valentina Zuco (ORCID: https://orcid.org/0000-0001-7882-9095)
- Nadia Zaffaroni (ORCID: https://orcid.org/0000-0002-4669-0890)
Institutions
- Memorial Sloan Kettering Cancer Center (US)
- Cornell University (US)
- Columbia University Irving Medical Center (US)
- Kettering University (US)
- Kyoto Prefectural University of Medicine (JP)
- Chan Zuckerberg Initiative (United States) (US)
- Fondazione IRCCS Istituto Nazionale dei Tumori (IT)
- Herbert Irving Comprehensive Cancer Center
- Columbia University (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-08-12
- DOI
- https://doi.org/10.1172/jci179282
- Citations
- 4
- Primary Topic
- Chromatin Remodeling and Cancer
- Type
- article
- Field-Weighted Citation Impact
- 3.22
Funders
- Ipsen
- National Institutes of Health