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

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, 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.

Leveraging homologous recombination repair deficiency in sarcoma

“…Their cancer samples included TCGA‐SARC (sarcoma) cohorts (247 cases) and TARGET‐OS (osteosarcoma) cohorts (69 cases), as well as five myxofibrosarcoma patients, 21 angiosarcoma patients and 282 soft tissue and bone sarcoma patients. Based on this comprehensive analysis, Planas‐Paz et al ( 2023 ) demonstrate HRD ness as a general feature of sarcomas. They report that BRCA2 and FANC genes are the most frequently mutated HR genes in sarcomas and find that a high HRD score is associated with HR gene mutations, increased HR gene expression and CIN.…”

“…In this manuscript, Planas‐Paz et al ( 2023 ) develop a personalised oncological approach based on a large‐scale bioinformatics and multi‐omics platform to analyse various features of HRDness in publicly available sarcoma databases and sarcoma patient samples (Fig. 1 ).…”

“…To test whether HRD ness can be used as a predictive biomarker for PARPi sensitivity in sarcomas, as previously shown for ovarian, breast, pancreatic, and prostate cancers (Nguyen et al , 2020 ), Planas‐Paz et al ( 2023 ) established patient‐derived sarcoma cell models with high or low HRD scores and tested their sensitivity to PARPi (olaparib and niraparib) and WEE1i (adavosertib) (Slade, 2020 ; Groelly et al , 2022 ). HRD high samples showed impaired RAD51 foci formation, in accordance with defective HR.…”

“…By treating a metastatic leiomyosarcoma patient with the PARPi olaparib combined with trabectedin, Planas‐Paz et al ( 2023 ) report that this led to partial remission and prolonged stable disease over a period of 18 months. This compelling proof of concept, along with ongoing clinical trials that are testing the benefits of combining targeted and chemotherapy in sarcomas, will undoubtedly instigate future clinical trials in which sarcoma patients should be stratified based on HRD as a biomarker guiding the choice of therapy.…”

“…Overall, the study by Planas‐Paz et al ( 2023 ) represents an important step in addressing an unmet need in advanced and refractory sarcomas by identifying HRD ness as a predictive biomarker for the efficiency of a combinatorial treatment strategy of PARPi and trabectedin or WEE1i and doxorubicin. Ongoing clinical trials ( https://clinicaltrials.gov ) with PARPi (olaparib/niraparib/talazoparib) alone or in combination with trabectedin, temozolomide (methylating agent), irinotecan (topoisomerase I inhibitor), POLθ inhibitors, ATR inhibitors or immune checkpoint inhibitors (durvalumab/dostarlimab), amongst others, will further probe the efficacy of PARP inhibitors in advanced and refractory sarcomas.…”