Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma. Issue 4 (13th February 2023)

• Record Type: Journal Article
• Authors: Planas‐Paz, Lara; Pliego‐Mendieta, Alicia; Hagedorn, Catherine; Aguilera‐Garcia, Domingo; Haberecker, Martina; Arnold, Fabian; Herzog, Marius; Bankel, Lorenz; Guggenberger, Roman; Steiner, Sabrina; Chen, Yanjiang; Kahraman, Abdullah; Zoche, Martin; Rubin, Mark A; Moch, Holger; Britschgi, Christian; Pauli, Chantal
• Is Part Of: EMBO molecular medicine. Volume 15:Issue 4(2023)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2023-02-13
• Subjects: genomic instability -- HRDness -- HRD score -- sarcoma; Molecular biology -- Periodicals; Medical genetics -- Periodicals; Pathology, Molecular -- Periodicals; 616.04205
• DOI: 10.15252/emmm.202216863
• Languages: English
• ISSNs: 1757-4676

Abstract

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 HRD ness traits exhibit a distinct SARC‐HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient‐derived sarcoma cells. Concomitantly, HRD high 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 HRD ness 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. Synopsis: Defects in the homologous recombination repair pathway causing HRD ness, often observed in breast, ovarian, prostate, and pancreatic cancer, can be detected in distinct sarcoma subtypes at the genomic and transcriptomic levels, and treated with DNA damage and repair‐based therapeutic approaches. Sarcoma entities with genomic traits of homologous recombination repair (HRR) deficiency (HRD ness ) were identified in multiple patient cohorts Sarcomas with HRD ness traits were shown to exhibit numerous alterations in HRR genes and chromosomal instability The SARC‐HRD transcriptional signature was identified in sarcomas with HRD ness and predicts PARP inhibitor sensitivity Patient‐derived sarcoma cell models with HRD ness respond to a combinatorial regimen of chemotherapy and agents targeting DNA damage and repair pathways Sarcoma patients can be efficaciously treated with PARP inhibitors in combination with standard‐of‐care chemotherapeutic agents Abstract : Defects in the homologous recombination repair pathway causing HRD ness, often observed in breast, ovarian, prostate and pancreatic cancer, can be detected in distinct sarcoma subtypes at the genomic and transcriptomic levels, and treated with DNA damage and repair‐based therapeutic approaches.