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

Yaniv Kazansky1,2, Helen S Mueller1,2, Daniel Cameron1,2

  • 1Molecular Pharmacology Program, Sloan Kettering Institute and.

The Journal of Clinical Investigation
|August 12, 2025
PubMed

Insights

Combining EZH2 and ATR inhibitors shows promise for treating cancers like epithelioid sarcoma. This epigenetic therapy targets DNA damage repair pathways, improving responses in preclinical models.

Area of Science:

  • Oncology
  • Epigenetics
  • Cancer Biology

Background:

  • Most cancers do not respond to current epigenetic drugs.
  • Tazemetostat, an EZH2 inhibitor, is approved for SMARCB1-deficient epithelioid sarcomas.
  • Understanding response and resistance to EZH2 inhibitors is crucial.

Purpose of the Study:

  • To identify novel combination epigenetic therapies for EZH2-resistant cancers.
  • To investigate the role of DNA damage repair in response to EZH2 inhibition.
  • To evaluate the efficacy of combined EZH2 and ATR inhibition.

Main Methods:

  • Transcriptomic inference in SMARCB1-deficient tumor cells.
  • Analysis of EZH2 inhibition-induced DNA damage and PGBD5 expression.
  • Inhibition of ATR kinase using elimusertib in patient-derived tumors.
  • In vivo efficacy studies in epithelioid and rhabdoid tumor models.

Main Results:

  • EZH2 inhibition induces DNA damage in epithelioid and rhabdoid tumor cells, partly via PGBD5.
  • A synthetic lethal dependency between EZH2 inhibition and PGBD5 was identified.
  • Combined EZH2 and ATR inhibition (elimusertib) demonstrated improved therapeutic responses.
  • ATR inhibition, not CHK1 inhibition, was effective in targeting PGBD5-dependent DNA damage.

Conclusions:

  • Combined EZH2 and ATR inhibition represents a rational epigenetic therapy strategy.
  • The EZH2-PGBD5 synthetic lethal dependency offers a target for novel cancer treatments.
  • This combination therapy is suitable for clinical trials in relevant patient populations.
Keywords:
Cell biologyDNA repairDrug therapyEpigeneticsOncology

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