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:

• Genetic loss of DNA damage response (DDR) genes creates vulnerabilities exploitable by synthetic lethality.
• FET family proteins are early responders to DNA double-strand breaks (DSBs).
• FET fusion oncoproteins are implicated in various sarcomas and leukemias.

Purpose of the Study:

• To investigate the role of FET proteins and FET fusion oncoproteins in DNA repair.
• To identify therapeutic vulnerabilities in FET-rearranged cancers, using Ewing sarcoma as a model.
• To explore the impact of EWSR1::FLI1 oncoprotein on DNA damage response pathways.

Main Methods:

• Utilized Ewing sarcoma as a model for FET-rearranged cancers.
• Investigated the recruitment of EWSR1::FLI1 and other FET fusion oncoproteins to DNA DSBs.
• Assessed the impact on ATM activation and signaling.
• Evaluated the compensatory ATR signaling axis.
• Tested ATR inhibitors in patient-derived xenograft models.

Main Results:

• Recruitment of FET fusion oncoproteins to DNA DSBs inhibits ATM activation and signaling.
• The ATR signaling axis becomes a collateral dependency in FET-rearranged cancers.
• ATR inhibition showed therapeutic potential in preclinical models of multiple FET-rearranged cancers.

Conclusions:

• Oncogenic proteins can disrupt normal DNA repair mechanisms.
• ATR signaling represents a promising therapeutic target for FET-rearranged cancers.
• These findings provide a preclinical basis for clinical trials of ATR inhibitors in these cancers.