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PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers
Reem Ali1, Muslim Alabdullah2, Adel Alblihy1
1Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK.
Abstract:
PARP1 inhibitor (Niraparib, Olaparib, Rucaparib) maintenance therapy improves progression-free survival in platinum sensitive sporadic epithelial ovarian cancers. However, biomarkers of response to PARPi therapy is yet to be clearly defined. XRCC1, a scaffolding protein, interacts with PARP1 during BER and SSBR. In a large clinical cohort of 525 sporadic ovarian cancers, high XRCC1 or high PARP1 protein levels was not only associated with aggressive phenotypes but was also significantly linked with poor progression-free survival (p = 0.048 & p = 0.001 respectively) and poor ovarian cancer-specific survival (p = 0.020 & p = 0.008 respectively). Pre-clinically, Olaparib and Talazoparib therapy were selectively toxic in XRCC1 deficient or knock-out platinum sensitive ovarian cancer cells in 2D and 3D models. Increased sensitivity was associated with DNA double-strand break accumulation, cell cycle arrest and apoptotic cell accumulation. We conclude that XRCC1 deficiency predicts sensitivity to PARP inhibitor therapy. PARP1 targeting is a promising new approach in XRCC1 deficient ovarian cancers.
Insights
High levels of XRCC1 or PARP1 protein indicate aggressive ovarian cancer and poor survival. XRCC1 deficiency predicts sensitivity to PARP inhibitor therapy, offering a new treatment strategy for ovarian cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Poly (ADP-ribose) polymerase inhibitors (PARPi) improve outcomes in platinum-sensitive ovarian cancer.
- Biomarkers for PARPi response remain undefined.
- XRCC1 is a scaffolding protein involved in DNA repair pathways with PARP1.
Purpose of the Study:
- To investigate the role of XRCC1 and PARP1 protein levels as biomarkers for PARPi therapy in ovarian cancer.
- To evaluate the therapeutic potential of PARPi in XRCC1-deficient ovarian cancer models.
Main Methods:
- Analysis of XRCC1 and PARP1 protein expression in a cohort of 525 sporadic ovarian cancers.
- Correlation of protein levels with clinical outcomes (progression-free survival, overall survival).
- Pre-clinical evaluation of PARPi (Olaparib, Talazoparib) sensitivity in XRCC1-deficient ovarian cancer cell lines (2D and 3D models).
Main Results:
- High XRCC1 or PARP1 protein levels were associated with aggressive tumor phenotypes.
- Elevated XRCC1 or PARP1 expression correlated significantly with poor progression-free survival and ovarian cancer-specific survival.
- XRCC1-deficient ovarian cancer cells exhibited increased sensitivity to Olaparib and Talazoparib, characterized by DNA double-strand breaks, cell cycle arrest, and apoptosis.
Conclusions:
- XRCC1 deficiency is a predictive biomarker for PARP inhibitor sensitivity in ovarian cancer.
- Targeting PARP1 is a promising therapeutic strategy for XRCC1-deficient ovarian cancers.
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