Work

Targeting ATR signaling in sarcoma with homologous recombination deficiency

Year: 2026

Type: article

Abstract: Homologous recombination deficiency (HRD) has emerged as a key vulnerability in selected cancer types and is associated with response to platinum and PARPi-based treatment strategies. However, additional biomarkers and targeted therapy options are needed to broaden the range of patients that could benefit from this therapeutic niche. Here, we show that the SARC-HRD signature, composed of ten genes of the homologous recombination repair pathway, stratifies a cohort of sarcoma patients, and associates with genomic biomarkers of HRD, with disease progression and with the CINSARC prognostic signature. Equivalently to CINSARC, high levels of SARC-HRD are associated with poor metastasis-free survival, underscoring the potential of SARC-HRD to predict disease outcome. By pharmacotyping patient-derived cell models, we identified promising drug targets within the DNA damage response for sarcoma with HRD traits. Inhibition of ATR, CHK1 and WEE1 elicited synthetic lethality in sarcoma cells with HRD, which concomitantly showed an upregulation of ATR signaling. Combinatorial drug testing further revealed synergistic drug combinations between ATRi, WEE1i, PARP1/2i and chemotherapeutic agents with potential clinical impact. Mechanistically, targeting ATR signaling at multiple levels induced a replication defect, mitotic abnormalities and apoptotic cell death. Taken together, our results demonstrate the therapeutic benefit of targeting DDR mechanisms in sarcoma with HRDness traits and their potential clinical utility for treating a broader spectrum of tumor types. • The SARC-HRD signature associates with HRD biomarkers and disease progression • Pharmacotyping uncovers DNA damage response mechanisms as potential sarcoma targets • Inhibition of ATR, CHK1 and WEE1 elicits synthetic lethality in HRD sarcoma cells • Combinatorial drug testing reveals synergistic drug combinations with clinical impact • Targeting ATR-CHK1 signaling induces replication defects, mitotic abnormalities and apoptotic cell death

Source: Cancer Letters

DOI: 10.1016/j.canlet.2026.218300