Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma
Abstract Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show...
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| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer Nature
2023-02-01
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| Series: | EMBO Molecular Medicine |
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| Online Access: | https://doi.org/10.15252/emmm.202216863 |
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| author | Lara Planas‐Paz Alicia Pliego‐Mendieta Catherine Hagedorn Domingo Aguilera‐Garcia Martina Haberecker Fabian Arnold Marius Herzog Lorenz Bankel Roman Guggenberger Sabrina Steiner Yanjiang Chen Abdullah Kahraman Martin Zoche Mark A Rubin Holger Moch Christian Britschgi Chantal Pauli |
| author_facet | Lara Planas‐Paz Alicia Pliego‐Mendieta Catherine Hagedorn Domingo Aguilera‐Garcia Martina Haberecker Fabian Arnold Marius Herzog Lorenz Bankel Roman Guggenberger Sabrina Steiner Yanjiang Chen Abdullah Kahraman Martin Zoche Mark A Rubin Holger Moch Christian Britschgi Chantal Pauli |
| author_sort | Lara Planas‐Paz |
| collection | DOAJ |
| description | Abstract Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC‐HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient‐derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully. |
| format | Article |
| id | doaj-art-d874520ba4d8464eacd895ed33371d67 |
| institution | Kabale University |
| issn | 1757-4676 1757-4684 |
| language | English |
| publishDate | 2023-02-01 |
| publisher | Springer Nature |
| record_format | Article |
| series | EMBO Molecular Medicine |
| spelling | doaj-art-d874520ba4d8464eacd895ed33371d672025-08-20T03:43:01ZengSpringer NatureEMBO Molecular Medicine1757-46761757-46842023-02-0115412110.15252/emmm.202216863Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcomaLara Planas‐Paz0Alicia Pliego‐Mendieta1Catherine Hagedorn2Domingo Aguilera‐Garcia3Martina Haberecker4Fabian Arnold5Marius Herzog6Lorenz Bankel7Roman Guggenberger8Sabrina Steiner9Yanjiang Chen10Abdullah Kahraman11Martin Zoche12Mark A Rubin13Holger Moch14Christian Britschgi15Chantal Pauli16Laboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichMolecular Tumor Profiling Laboratory, Department of Pathology and Molecular Pathology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichMolecular Tumor Profiling Laboratory, Department of Pathology and Molecular Pathology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichDepartment of Medical Oncology and Haematology, University Hospital ZurichDiagnostic and Interventional Radiology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichMolecular Tumor Profiling Laboratory, Department of Pathology and Molecular Pathology, University Hospital ZurichMolecular Tumor Profiling Laboratory, Department of Pathology and Molecular Pathology, University Hospital ZurichPrecision Oncology Laboratory, Department for Biomedical Research, Bern Center for Precision MedicineLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichDepartment of Medical Oncology and Haematology, University Hospital ZurichLaboratory for Systems Pathology and Functional Tumor Pathology, Department of Pathology and Molecular Pathology, University Hospital ZurichAbstract Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC‐HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient‐derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.https://doi.org/10.15252/emmm.202216863genomic instabilityHRDnessHRD scoresarcoma |
| spellingShingle | Lara Planas‐Paz Alicia Pliego‐Mendieta Catherine Hagedorn Domingo Aguilera‐Garcia Martina Haberecker Fabian Arnold Marius Herzog Lorenz Bankel Roman Guggenberger Sabrina Steiner Yanjiang Chen Abdullah Kahraman Martin Zoche Mark A Rubin Holger Moch Christian Britschgi Chantal Pauli Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma EMBO Molecular Medicine genomic instability HRDness HRD score sarcoma |
| title | Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| title_full | Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| title_fullStr | Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| title_full_unstemmed | Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| title_short | Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| title_sort | unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma |
| topic | genomic instability HRDness HRD score sarcoma |
| url | https://doi.org/10.15252/emmm.202216863 |
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