Targeting ATR signaling in sarcoma with homologous recombination deficiency

  • Cancer Lett. 2026 Apr 1:642:218300. doi: 10.1016/j.canlet.2026.218300.
L Planas-Paz  1 ,  M Zehnder  2 ,  N Desboeufs  3 ,  S Kollar  2 ,  Y Chen  2 ,  S Schneebeli  2 ,  R Schenk  2 ,  M P Schmid  2 ,  M Lopes  4 ,  A Weber  5 ,  C Pauli  6
Affiliations
  • 1. Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland. Electronic address: [email protected].
  • 2. Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland.
  • 3. Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Institute of Molecular Cancer Research (IMCR), University of Zurich, Zurich, Switzerland.
  • 4. Institute of Molecular Cancer Research (IMCR), University of Zurich, Zurich, Switzerland; Medical Faculty, University of Zurich, Zurich, Switzerland.
  • 5. Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Institute of Molecular Cancer Research (IMCR), University of Zurich, Zurich, Switzerland; Medical Faculty, University of Zurich, Zurich, Switzerland.
  • 6. Department of Pathology and Molecular Pathology, University of Zurich and University Hospital Zurich, Zurich, Switzerland; Medical Faculty, University of Zurich, Zurich, Switzerland. Electronic address: [email protected].
PMID: 41651400 DOI: 10.1016/j.canlet.2026.218300
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 (DDR) 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.

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