Abstract 109P
Background
Defects in homologous recombination repair (HRR) in tumours correlate with poor prognosis and metastases development. Determining HRR deficiency (HRDness) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Sarcomas are rare mesenchymal cancers, accounting for approximately 1% of all malignancies. Standard of care mostly relies on chemotherapy but sarcoma often show chemoresistance and metastatic disease is associated with a poor prognosis. There is an increasing emphasis on understanding the cancer biology of individual sarcoma subtypes to inform the development of personalized targeted treatment approaches.
Methods
We investigated genomic and transcriptomic features of HRDness in sarcoma and cross-validated our findings among several datasets. We established and molecularly profiled eight patient-derived ex vivo sarcoma cell models. We functionally tested the sensitivity of our models to several targeted therapies including PARPi as gold standard treatment for HRDness and chemotherapies in six-point dose response curves either in monotherapy or in combination.
Results
We show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harbouring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARPi 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.
Conclusions
We show that a subset of sarcoma entities exhibit features of HRDness at the genomic and transcriptomic level and highlight the need to characterize sarcoma patients with multiple parameters to better identify those with HRDness. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
The authors.
Funding
Swiss Cancer Research Foundation [KFS-5270-02-2021] and the Olga Mayenfisch Foundation.
Disclosure
All authors have declared no conflicts of interest.