PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers.

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.

• Authors: Reem Ali, Muslim Alabdullah, Adel Alblihy, Islam Miligy, Katia A Mesquita, Stephen Yt Chan, Paul Moseley, Emad A Rakha, Srinivasan Madhusudan
• Journal: Cancer letters (Cancer Lett) Vol. 469 Pg. 124-133 (01 28 2020) ISSN: 1872-7980 [Electronic] Ireland
• PMID: 31669203 (Publication Type: Journal Article)
• Copyright: Copyright © 2019 Elsevier B.V. All rights reserved.

Chemical References

• Phthalazines
• Piperazines
• Poly(ADP-ribose) Polymerase Inhibitors
• X-ray Repair Cross Complementing Protein 1
• XRCC1 protein, human
• talazoparib
• PARP1 protein, human
• Poly (ADP-Ribose) Polymerase-1
• olaparib

Topics

• Carcinoma, Ovarian Epithelial (drug therapy, genetics, mortality, pathology)
• Cell Cycle Checkpoints (drug effects, genetics)
• Cell Line, Tumor
• DNA Breaks, Double-Stranded (drug effects)
• Drug Resistance, Neoplasm (genetics)
• Female
• Follow-Up Studies
• Gene Expression Profiling
• Gene Knockout Techniques
• Humans
• Kaplan-Meier Estimate
• Ovarian Neoplasms (drug therapy, genetics, mortality, pathology)
• Ovary (pathology)
• Phthalazines (pharmacology, therapeutic use)
• Piperazines (pharmacology, therapeutic use)
• Poly (ADP-Ribose) Polymerase-1 (antagonists & inhibitors, metabolism)
• Poly(ADP-ribose) Polymerase Inhibitors (pharmacology, therapeutic use)
• Prognosis
• Progression-Free Survival
• Synthetic Lethal Mutations (drug effects)
• Tissue Array Analysis
• X-ray Repair Cross Complementing Protein 1 (deficiency, genetics)