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Title: | FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers | Authors: | Mesquita, Katia A. Doherty, Rachel Toss, Michael S. Miligy, Islam Alblihy, Adel Dorjsuren, Dorjbal Simeonov, Anton Jadhav, Ajit WILSON, David Hickson, Ian Tatum, Natalie J. Rakha, Emad A. Madhusudan, Srinivasan Reem, Ali |
Issue Date: | 2021 | Publisher: | MDPI | Source: | Cancers, 13 (8) (Art N° 1866) | Abstract: | Simple Summary Overall survival outcomes, despite platinum-based chemotherapy, for patients with advanced ovarian cancer remains poor. Increased DNA repair capacity is a key route to platinum resistance in ovarian cancer. In the current study, we show that FEN1, a key player in DNA repair, is overexpressed in ovarian cancer and associated with poor survival. Pre-clinically FEN1 blockade not only increased platinum sensitivity but was also synthetically lethal in BRCA2 and POL beta deficient ovarian cancer cells. Together the data provides evidence that FEN1 is a promising anti-cancer target in ovarian cancer. FEN1 plays critical roles in long patch base excision repair (LP-BER), Okazaki fragment maturation, and rescue of stalled replication forks. In a clinical cohort, FEN1 overexpression is associated with aggressive phenotype and poor progression-free survival after platinum chemotherapy. Pre-clinically, FEN1 is induced upon cisplatin treatment, and nuclear translocation of FEN1 is dependent on physical interaction with importin beta. FEN1 depletion, gene inactivation, or inhibition re-sensitizes platinum-resistant ovarian cancer cells to cisplatin. BRCA2 deficient cells exhibited synthetic lethality upon treatment with a FEN1 inhibitor. FEN1 inhibitor-resistant PEO1R cells were generated, and these reactivated BRCA2 and overexpressed the key repair proteins, POL beta and XRCC1. FEN1i treatment was selectively toxic to POL beta deficient but not XRCC1 deficient ovarian cancer cells. High throughput screening of 391,275 compounds identified several FEN1 inhibitor hits that are suitable for further drug development. We conclude that FEN1 is a valid target for ovarian cancer therapy. | Notes: | Madhusudan, S (corresponding author), Univ Nottingham, Sch Med, Div Canc & Stem Cells, Translat Oncol,Biodiscovery Inst, Nottingham NG7 2RD, England.; Madhusudan, S (corresponding author), Nottingham Univ Hosp, Dept Oncol, City Hosp Campus, Nottingham NG5 1PB, England. mesquita.al0602@gmail.com; reem.ali1@nottingham.ac.uk; rejdoherty@aol.com; michael.shawkytoss@nottingham.ac.uk; islam.abdelaziz@nottingham.ac.uk; adel.alblihy@nottingham.ac.uk; dorjsurend@mail.nih.gov; asimeono@mail.nih.gov; ajit.jadhav@gmail.com; david.wilson@uhasselt.be; Ian.Hickson@newcastle.ac.uk; Natalie.tatum@newcastle.ac.uk; mrzear1@exmail.nottingham.ac.uk; srinivasan.madhusudan@nottingham.ac.uk |
Other: | Madhusudan, S (corresponding author), Univ Nottingham, Sch Med, Div Canc & Stem Cells, Translat Oncol,Biodiscovery Inst, Nottingham NG7 2RD, England ; Nottingham Univ Hosp, Dept Oncol, City Hosp Campus, Nottingham NG5 1PB, England. mesquita.al0602@gmail.com; reem.ali1@nottingham.ac.uk; rejdoherty@aol.com; michael.shawkytoss@nottingham.ac.uk; islam.abdelaziz@nottingham.ac.uk; adel.alblihy@nottingham.ac.uk; dorjsurend@mail.nih.gov; asimeono@mail.nih.gov; ajit.jadhav@gmail.com; david.wilson@uhasselt.be; Ian.Hickson@newcastle.ac.uk; Natalie.tatum@newcastle.ac.uk; mrzear1@exmail.nottingham.ac.uk; srinivasan.madhusudan@nottingham.ac.uk | Keywords: | ovarian cancer;FEN1;cisplatin sensitivity;DNA repair inhibitor;synthetic lethality | Document URI: | http://hdl.handle.net/1942/34145 | ISSN: | 2072-6694 | e-ISSN: | 2072-6694 | DOI: | 10.3390/cancers13081866 | ISI #: | WOS:000644005800001 | Rights: | 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/). | Category: | A1 | Type: | Journal Contribution | Validations: | ecoom 2022 |
Appears in Collections: | Research publications |
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cancers-13-01866.pdf | Published version | 5.58 MB | Adobe PDF | View/Open |
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