Targeting ATR signaling in sarcoma with homologous recombination deficiency

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Homologous recombination deficiency (HRD) is a key cancer vulnerability linked to platinum and PARP inhibitor (PARPi) treatment response.
• There is a need for additional biomarkers and targeted therapies to expand the benefits of HRD-targeted treatments to more patients.

Purpose of the Study:

• To investigate the SARC-HRD gene signature as a biomarker in sarcoma.
• To identify novel therapeutic targets within the DNA damage response (DDR) pathway for HRD-positive sarcomas.

Main Methods:

• Developed and validated the SARC-HRD signature, comprising ten homologous recombination repair pathway genes.
• Stratified sarcoma patients using the SARC-HRD signature and correlated it with genomic HRD biomarkers and disease progression.
• Utilized pharmacotyping of patient-derived cell models to identify drug targets and tested drug combinations, including ATR inhibitors (ATRi), WEE1 inhibitors (WEE1i), and PARP1/2 inhibitors (PARPi).

Main Results:

• The SARC-HRD signature effectively stratified sarcoma patients and correlated with genomic HRD biomarkers and poor metastasis-free survival, similar to the CINSARC signature.
• Inhibition of ATR, CHK1, and WEE1 demonstrated synthetic lethality in HRD-positive sarcoma cells, which exhibited upregulated ATR signaling.
• Combinatorial drug testing revealed synergistic effects between ATRi, WEE1i, PARPi, and chemotherapeutic agents, leading to replication defects, mitotic abnormalities, and apoptosis.

Conclusions:

• The SARC-HRD signature is a valuable prognostic biomarker for sarcoma, predicting disease outcome.
• Targeting DDR mechanisms, particularly ATR signaling, offers therapeutic benefits for sarcomas with HRD traits.
• These findings support the clinical utility of DDR-targeting strategies for a broader range of tumor types beyond current indications.