Next Article in Journal
Gene Amplification-Associated Overexpression of the Selenoprotein tRNA Enzyme TRIT1 Confers Sensitivity to Arsenic Trioxide in Small-Cell Lung Cancer
Next Article in Special Issue
KEAP1 Is Required for Artesunate Anticancer Activity in Non-Small-Cell Lung Cancer
Previous Article in Journal
Tyrosine Kinase c-MET as Therapeutic Target for Radiosensitization of Head and Neck Squamous Cell Carcinomas
Previous Article in Special Issue
Sensitivity and Resistance of Oncogenic RAS-Driven Tumors to Dual MEK and ERK Inhibition
Open AccessArticle

FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers

1
Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG7 2RD, UK
2
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG7 2RD, UK
3
Medical Center, King Fahad Security College (KFSC), Riyadh 11461, Saudi Arabia
4
NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, MD 20850, USA
5
Biomedical Research Institute, Hasselt University, 3590 Diepenbeek, Belgium
6
Cancer Research UK Newcastle Drug Discovery Unit, Newcastle University Centre for Cancer, Faculty of Medical Sciences, Newcastle University, Newcastle upon Tyne NE2 4HH, UK
7
Department of Oncology, Nottingham University Hospitals, City Hospital Campus, Nottingham NG5 1PB, UK
*
Author to whom correspondence should be addressed.
Academic Editors: Carlos M. Telleria and Zhixiang Wang
Cancers 2021, 13(8), 1866; https://doi.org/10.3390/cancers13081866
Received: 16 February 2021 / Revised: 18 March 2021 / Accepted: 5 April 2021 / Published: 14 April 2021
(This article belongs to the Collection Drug Resistance and Novel Therapies in Cancers)
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 POLβ 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 β. 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, POLβ and XRCC1. FEN1i treatment was selectively toxic to POLβ 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. View Full-Text
Keywords: ovarian cancer; FEN1; cisplatin sensitivity; DNA repair inhibitor; synthetic lethality ovarian cancer; FEN1; cisplatin sensitivity; DNA repair inhibitor; synthetic lethality
Show Figures

Graphical abstract

MDPI and ACS Style

Mesquita, K.A.; Ali, R.; Doherty, R.; Toss, M.S.; Miligy, I.; Alblihy, A.; Dorjsuren, D.; Simeonov, A.; Jadhav, A.; Wilson, D.M., III; Hickson, I.; Tatum, N.J.; Rakha, E.A.; Madhusudan, S. FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers. Cancers 2021, 13, 1866. https://doi.org/10.3390/cancers13081866

AMA Style

Mesquita KA, Ali R, Doherty R, Toss MS, Miligy I, Alblihy A, Dorjsuren D, Simeonov A, Jadhav A, Wilson DM III, Hickson I, Tatum NJ, Rakha EA, Madhusudan S. FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers. Cancers. 2021; 13(8):1866. https://doi.org/10.3390/cancers13081866

Chicago/Turabian Style

Mesquita, Katia A.; Ali, Reem; Doherty, Rachel; Toss, Michael S.; Miligy, Islam; Alblihy, Adel; Dorjsuren, Dorjbal; Simeonov, Anton; Jadhav, Ajit; Wilson, David M., III; Hickson, Ian; Tatum, Natalie J.; Rakha, Emad A.; Madhusudan, Srinivasan. 2021. "FEN1 Blockade for Platinum Chemo-Sensitization and Synthetic Lethality in Epithelial Ovarian Cancers" Cancers 13, no. 8: 1866. https://doi.org/10.3390/cancers13081866

Find Other Styles
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

1
Search more from Scilit
 
Search
Back to TopTop