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

Reem Ali; Muslim Alabdullah; Adel Alblihy; Islam Miligy; Katia A Mesquita; Stephen Yt Chan; Paul Moseley; Emad A Rakha; Srinivasan Madhusudan

doi:10.1016/j.canlet.2019.10.035

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

Cancer Lett. 2020 Jan 28:469:124-133. doi: 10.1016/j.canlet.2019.10.035. Epub 2019 Oct 24.

Authors

Reem Ali¹, Muslim Alabdullah², Adel Alblihy¹, Islam Miligy³, Katia A Mesquita¹, Stephen Yt Chan⁴, Paul Moseley⁴, Emad A Rakha³, Srinivasan Madhusudan⁵

Affiliations

¹ Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK.
² Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK; Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG51PB, UK.
³ Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham, NG51PB, UK.
⁴ Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK.
⁵ Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham, Nottingham University Hospitals, Nottingham, NG5 1PB, UK; Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK. Electronic address: [email protected].

PMID: 31669203
DOI: 10.1016/j.canlet.2019.10.035

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.

Keywords: Ovarian cancer; PARP; Synthetic lethality; XRCC1.

MeSH terms

Carcinoma, Ovarian Epithelial / drug therapy*
Carcinoma, Ovarian Epithelial / genetics
Carcinoma, Ovarian Epithelial / mortality
Carcinoma, Ovarian Epithelial / pathology
Cell Cycle Checkpoints / drug effects
Cell Cycle Checkpoints / 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*
Ovarian Neoplasms / genetics
Ovarian Neoplasms / mortality
Ovarian Neoplasms / pathology
Ovary / pathology
Phthalazines / pharmacology
Phthalazines / therapeutic use
Piperazines / pharmacology
Piperazines / therapeutic use
Poly (ADP-Ribose) Polymerase-1 / antagonists & inhibitors
Poly (ADP-Ribose) Polymerase-1 / metabolism
Poly(ADP-ribose) Polymerase Inhibitors / pharmacology*
Poly(ADP-ribose) Polymerase Inhibitors / therapeutic use
Prognosis
Progression-Free Survival
Synthetic Lethal Mutations / drug effects
Tissue Array Analysis
X-ray Repair Cross Complementing Protein 1 / deficiency*
X-ray Repair Cross Complementing Protein 1 / genetics

Substances

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