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

TitleEpigenetic targeting of PGBD5-dependent DNA damage in SMARCB1-deficient sarcomas.
Publication TypeJournal Article
Year of Publication2024
AuthorsKazansky Y, Mueller HS, Cameron D, Demarest P, Zaffaroni N, Arrighetti N, Zuco V, Mundi PS, Kuwahara Y, Somwar R, Qu R, Califano A, de Stanchina E, Cruz FSDela, Kung AL, Gounder MM, Kentsis A
JournalbioRxiv
Date Published2024 May 06
ISSN2692-8205
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 loss of 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 nominate the DNA damage repair kinase ATR as a target for rational combination EZH2 epigenetic therapy. We show that EZH2 inhibition promotes DNA damage in epithelioid and rhabdoid tumor cells, at least in part via its induction of the transposase-derived PGBD5. We leverage this collateral synthetic lethal dependency to target PGBD5-dependent DNA damage by inhibition of ATR but not CHK1 using elimusertib. Consequently, combined EZH2 and ATR inhibition improves 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.

DOI10.1101/2024.05.03.592420
Alternate JournalbioRxiv
PubMed ID38766189
PubMed Central IDPMC11100591
Grant ListP30 CA008748 / CA / NCI NIH HHS / United States
P50 CA217694 / CA / NCI NIH HHS / United States
R01 CA214812 / CA / NCI NIH HHS / United States
T32 GM007739 / GM / NIGMS NIH HHS / United States

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