Targeting ATR signaling in sarcoma with homologous recombination deficiency

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.