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
Stephen YT. Chan
Emad A. Rakha
SRINIVASAN MADHUSUDAN email@example.com
Professor of Medical Oncology
© 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|
|Peer Reviewed||Peer Reviewed|
|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|
|Keywords||Cancer Research; Oncology|
This file is under embargo until Oct 25, 2020 due to copyright restrictions.
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