FET fusion oncoproteins disrupt physiologic DNA repair and create a targetable opportunity for ATR inhibitor therapy

Area of Science:

• Oncology
• Molecular Biology
• Cancer Genetics

Background:

• Oncogenes promote cancer growth, but this proliferation stresses cellular homeostasis, including the DNA damage response (DDR).
• Cancers often disable tumor-suppressive DDR signaling via mutations (e.g., ATM, p53) to tolerate oncogene-driven growth.
• It remains unknown if oncogenes can induce functional defects in DDR networks to facilitate self-tolerance.

Purpose of the Study:

• To investigate how oncogenes, specifically the EWSR1-FLI1 fusion oncoprotein in Ewing sarcoma, impact DNA double-strand break (DSB) repair.
• To determine the role of FET family proteins and FET fusion oncoproteins in DNA repair pathways.
• To identify potential therapeutic vulnerabilities arising from oncogene-induced DDR defects.

Main Methods:

• Focus on Ewing sarcoma as a model for FET-rearranged cancers.
• Investigate the recruitment of EWSR1-FLI1 to DNA double-strand breaks (DSBs).
• Analyze the interaction between EWSR1-FLI1 and native FET proteins (EWSR1) in ATM activation.
• Examine ATM and ATR signaling pathways in FET-rearranged cancers.

Main Results:

• The EWSR1-FLI1 oncoprotein is recruited to DSBs.
• EWSR1-FLI1 interferes with native EWSR1 function in activating the ATM DNA damage sensor.
• FET fusion oncoproteins induce functional ATM defects in various FET-rearranged cancers.
• The ATR signaling axis becomes a collateral dependency and therapeutic target due to ATM defects.

Conclusions:

• Aberrant recruitment of fusion oncoproteins to DNA damage sites can disrupt physiologic DSB repair.
• Growth-promoting oncogenes can create functional defects within tumor-suppressive DDR networks.
• Targeting the ATR signaling axis presents a therapeutic strategy for FET-rearranged cancers.