Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma

Autor: 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
Jazyk: angličtina
Rok vydání: 2023
Předmět:
Zdroj: EMBO Molecular Medicine, Vol 15, Iss 4, Pp 1-21 (2023)
Druh dokumentu: article
ISSN: 1757-4676
1757-4684
DOI: 10.15252/emmm.202216863
Popis: 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.
Databáze: Directory of Open Access Journals
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