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

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

Authors

Katia A. Mesquita

Reem Ali

Stephen YT. Chan

Muslim Alabdullah

Adel Alblihy

Islam Miligy

Paul Moseley

Emad A. Rakha



Abstract

© 2019 Elsevier B.V. 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.

Journal Article Type Article
Publication Date Jan 28, 2020
Journal Cancer Letters
Print ISSN 0304-3835
Electronic ISSN 1872-7980
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 469
Pages 124-133
APA6 Citation Mesquita, K. A., Ali, R., Chan, S. Y., Alabdullah, M., Alblihy, A., Miligy, I., …Madhusudan, S. (2020). PARP1 blockade is synthetically lethal in XRCC1 deficient sporadic epithelial ovarian cancers. Cancer Letters, 469, 124-133. https://doi.org/10.1016/j.canlet.2019.10.035
DOI https://doi.org/10.1016/j.canlet.2019.10.035
Keywords Cancer Research; Oncology
Publisher URL https://www.sciencedirect.com/science/article/pii/S0304383519305385
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