Background: Defects in the homologous recombination repair (HRR) pathway have been frequently observed in high-grade ovarian, breast, pancreatic and prostate carcinomas.HRR deficiency (HRD) has emerged as a key therapeutic vulnerability by exploiting the concept of synthetic lethality.Targeting PARP proteins causes cells to rely on other pathways for repairing double-strand DNA breaks.When cells lack functional BRCA1/2 genes or exhibit a compromised HRR pathway, they become sensitive to PARP inhibition (PARPi), while cells with an intact HRR pathway are unaffected.This treatment option is yet to be employed across a broader range of malignancies with HRD traits, like distinct sarcoma subtypes, colorectal carcinoma and hepatocellular carcinoma. Methods:We combined molecular profiling of patients with pharmacotyping of patient-derived sarcoma cells and validated a gene expression signature as predictive biomarker of drug response.Results: Here, we investigated the predictive and prognostic biomarker value of transcriptomic signatures in sarcoma as well as discovered novel therapeutic opportunities within the DDR for soft tissue sarcoma.Firstly, we validated SARC-HRD differential expression in soft tissue sarcoma with HRD traits using an independent cohort.We found a high correlation between SARC-HRD and CINSARC transcriptomic signatures in sarcoma, both associated with poor clinical outcome.Secondly, we performed mid-throughput drug screening in ex vivo patient-derived sarcoma cell models, expressing high levels of both transcriptomic signatures, and identified small inhibitors targeting ATR, CHK1 and WEE1, as single agents or in combination, as promising new treatment strategies for sarcoma patients.Lastly, we showed mechanistically a slowdown of the DNA replication fork upon treatment with selected DDR inhibitors as well as increased ATR pathway activation in sarcoma cell models sensitive to these drugs. Conclusions:In summary, we showed the value of transcriptomic signatures in predicting drug response and offer potential new venues for clinical management of tumors with HRD.
Karademir-Yilmaz et al. (Sun,) studied this question.