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

Area of Science:

• Oncology
• Epigenetics
• Cancer Biology

Background:

• Most cancers do not respond to current epigenetic drugs, limiting their therapeutic potential.
• Tazemetostat, an EZH2 inhibitor, is approved for SMARCB1-deficient epithelioid sarcomas due to functional antagonism between PRC2 and SMARCB1 loss.
• Previous studies defined response and resistance principles to EZH2 epigenetic therapy in patient tumors.

Approach:

• Transcriptomic inference from SMARCB1-deficient tumor cells identified ATR, a DNA damage repair kinase, as a rational combination target for EZH2 epigenetic therapy.
• Investigated the mechanism by which EZH2 inhibition promotes DNA damage, partly via induction of the transposase-derived PGBD5.
• Leveraged the synthetic lethal dependency between PGBD5 and DNA damage by inhibiting ATR (not CHK1) with elimusertib.

Key Points:

• EZH2 inhibition induces DNA damage in epithelioid and rhabdoid tumor cells, mediated in part by PGBD5.
• Combined EZH2 and ATR inhibition demonstrates improved therapeutic responses in diverse patient-derived epithelioid and rhabdoid tumors.
• This combination therapy exploits an EZH2-PGBD5 synthetic lethal dependency.

Conclusions:

• The combination of EZH2 and ATR inhibition offers a rational approach for treating specific cancer types.
• This strategy is suitable for translation to clinical trials for patients with relevant tumor types.
• Advances a novel combination epigenetic therapy based on a synthetic lethal dependency.