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 (2023). Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma. EMBO molecular medicine, 15(4), e16863. EMBO Press 10.15252/emmm.202216863
|
Text
planas-paz-et-al-2023-unravelling-homologous-recombination-repair-deficiency-and-therapeutic-opportunities-in-soft.pdf - Published Version Available under License Creative Commons: Attribution (CC-BY). Download (15MB) | Preview |
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.
Item Type: |
Journal Article (Original Article) |
|---|---|
Division/Institute: |
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) |
UniBE Contributor: |
Rubin, Mark Andrew |
Subjects: |
600 Technology > 610 Medicine & health |
ISSN: |
1757-4684 |
Publisher: |
EMBO Press |
Language: |
English |
Submitter: |
Andrea Stettler |
Date Deposited: |
29 Dec 2023 09:13 |
Last Modified: |
29 Dec 2023 09:21 |
Publisher DOI: |
10.15252/emmm.202216863 |
PubMed ID: |
36779660 |
Uncontrolled Keywords: |
HRD score HRDness genomic instability sarcoma |
BORIS DOI: |
10.48350/190974 |
URI: |
https://boris.unibe.ch/id/eprint/190974 |
Actions (login required)
 |
Edit item |