Replication Stress Is an Actionable Genetic Vulnerability in Desmoplastic Small Round Cell Tumors

Area of Science:

• Oncology
• Molecular Biology
• Genetics

Background:

• Desmoplastic small round cell tumor (DSRCT) is an aggressive sarcoma with a poor prognosis and limited treatment advancements.
• The EWS-WT1 chimeric transcription factor is the primary driver of DSRCT.

Purpose of the Study:

• To identify effective therapeutic strategies for DSRCT by screening small-molecule inhibitors.
• To investigate the therapeutic potential of PARP inhibitors (PARPi) and ATR inhibitors (ATRi) in DSRCT models.

Main Methods:

• Conducted a high-throughput drug sensitivity screen of 79 small-molecule inhibitors in a DSRCT cell line.
• Validated the efficacy of PARPi and ATRi in multiple DSRCT models, including cell lines, organoids, and xenografts.
• Investigated the underlying molecular mechanisms, including DNA damage, replication stress, and R-loop formation.

Main Results:

• DSRCT cells demonstrated sensitivity to PARPi and ATRi as monotherapies and in combination.
• Combined PARPi and ATRi treatment induced significant DNA damage, replication stress, and R-loop accumulation.
• EWS-WT1 silencing reversed sensitivity to PARPi and ATRi, highlighting its role in drug vulnerability.
• PARPi and ATRi combination therapy activated innate immune pathways and increased PD-L1 expression.

Conclusions:

• EWS-WT1 drives R-loop-dependent replication stress, creating a targetable vulnerability in DSRCT.
• PARPi and ATRi represent a promising therapeutic strategy for DSRCT patients.
• Clinical trials of PARPi and ATRi are warranted for DSRCT treatment.