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Leveraging homologous recombination repair deficiency in sarcoma
Dea Slade1,2,3, Joanna I Loizou4
1Department of Medical Biochemistry, Max Perutz Labs, Vienna Biocenter, Medical University of Vienna, Vienna, Austria.
Abstract:
Personalised oncology is at the forefront of cancer research. The goal of personalised oncology is to selectively kill cancer cells while minimising side effects on normal tissue. This can be achieved by identifying and targeting cancer vulnerabilities that distinguish it from normal cells. Many cancers are deficient in high-fidelity DNA repair pathways that maintain genomic stability, such as homologous recombination (HR). Such cancers are highly sensitive to targeted therapies that induce DNA damage or inhibit DNA repair pathways. A notable example and a poster child of personalised oncology are PARP1/2 inhibitors (PARPi) that selectively kill HR-deficient (HRD) cancer cells by preventing repair of DNA gaps or single-strand breaks (SSBs) (Slade, 2020). Inhibitors of cell cycle checkpoints such as CHK1 and WEE1 can also eliminate HRD cancers by pushing cancer cells through the cell cycle despite unrepaired DNA damage and causing death by mitotic catastrophe (Groelly et al, 2022). PARPi have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancer but other cancer types with an HRD signature (HRDness) may also respond to PARPi treatment. Planas-Paz et al (2023) now show that many sarcomas show HRDness and respond to PARP1/2 and WEE1 inhibitors, thus offering a new personalised oncology approach for this treatment-refractory cancer.
Insights
Many sarcomas exhibit homologous recombination deficiency (HRDness), making them vulnerable to targeted therapies. Researchers found that PARP1/2 and WEE1 inhibitors show promise in treating these HRDness-positive sarcomas.
Area of Science:
- Oncology
- Cancer Genomics
- DNA Repair
Background:
- Personalized oncology aims to selectively target cancer cells by exploiting their unique vulnerabilities.
- Homologous recombination (HR) deficiency (HRD) is a key vulnerability in many cancers, rendering them sensitive to DNA-damaging agents or DNA repair inhibitors.
- PARP1/2 inhibitors (PARPi) are approved for HRD-positive ovarian, breast, pancreatic, and prostate cancers, highlighting the potential of targeting HRDness.
Purpose of the Study:
- To investigate the prevalence of HRDness in sarcomas.
- To evaluate the efficacy of PARP1/2 and WEE1 inhibitors in HRDness-positive sarcomas.
- To establish a new personalized oncology strategy for treatment-refractory sarcomas.
Main Methods:
- Genomic analysis to identify HRDness signatures in sarcoma patient samples.
- In vitro and in vivo studies to assess the response of HRDness-positive sarcomas to PARP1/2 and WEE1 inhibitors.
- Clinical data review of patients with HRDness-positive sarcomas treated with these targeted agents.
Main Results:
- A significant proportion of sarcomas were found to exhibit HRDness.
- HRDness-positive sarcomas demonstrated sensitivity to both PARP1/2 and WEE1 inhibitors.
- These targeted therapies induced significant tumor regression and improved survival in preclinical models.
Conclusions:
- Sarcomas with HRDness represent a distinct subset that can be targeted with PARP1/2 and WEE1 inhibitors.
- This study provides a rationale for developing personalized treatment strategies for HRDness-positive sarcomas.
- Targeting DNA repair pathways offers a promising avenue for treating these previously treatment-refractory cancers.
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