Unravelling homologous recombination repair deficiency and therapeutic opportunities in soft tissue and bone sarcoma.
Lara Planas-PazAlicia Pliego-MendietaCatherine HagedornDomingo Aguilera-GarciaMartina HabereckerFabian M ArnoldMarius HerzogLorenz BankelRoman GuggenbergerSabrina SteinerYanjiang ChenAlexandre ThiéryMartin ZocheMark A RubinHolger MochChristian BritschgiChantal PauliPublished in: EMBO molecular medicine (2023)
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, 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 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.
Keyphrases
- dna repair
- dna damage
- poor prognosis
- induced apoptosis
- dna damage response
- oxidative stress
- long non coding rna
- genome wide
- soft tissue
- cell cycle arrest
- newly diagnosed
- primary care
- end stage renal disease
- gene expression
- endoplasmic reticulum stress
- copy number
- ejection fraction
- replacement therapy
- dna methylation
- cell proliferation
- prostate cancer
- signaling pathway
- smoking cessation
- rectal cancer
- circulating tumor
- high speed
- circulating tumor cells