Katia A. Mesquita
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
Reem Ali
Stephen YT. Chan
Muslim Alabdullah
Adel Alblihy
Islam Miligy
Paul Moseley
Emad A. Rakha
SRINIVASAN MADHUSUDAN srinivasan.madhusudan@nottingham.ac.uk
Professor of Medical Oncology
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.
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
Journal Article Type | Article |
---|---|
Acceptance Date | Oct 21, 2019 |
Online Publication Date | Oct 24, 2019 |
Publication Date | Jan 28, 2020 |
Deposit Date | Oct 28, 2019 |
Publicly Available Date | Mar 28, 2024 |
Journal | Cancer Letters |
Print ISSN | 0304-3835 |
Electronic ISSN | 1872-7980 |
Publisher | Elsevier |
Peer Reviewed | Peer Reviewed |
Volume | 469 |
Pages | 124-133 |
DOI | https://doi.org/10.1016/j.canlet.2019.10.035 |
Keywords | Cancer Research; Oncology |
Public URL | https://nottingham-repository.worktribe.com/output/2977672 |
Publisher URL | https://www.sciencedirect.com/science/article/pii/S0304383519305385 |
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