Targeting flap endonuclease 1 (FEN1) for personalization of ovarian cancer therapy


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Reem Ali1,Dorjbal Dorjsuren2,David Maloney2,Ajit Jadhav2,Anton Simeonov2,David Wilson III3,Anna Grabowska1,Emad Rakha1,Srinivasan Madhusudan1
1Division of Cancer & Stem Cells, School of Medicine, University of Nottingham, UK,2NIH Chemical Genomics Center, National Center for Advancing Translational Sciences, National Institutes of Health, 9800 Medical Center Drive, Rockville, Maryland 20850, USA,3Laboratory of Molecular Gerontology, Biomedical Research Center, National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224-6825, USA

Abstract

Background

The clinical use of PARP inhibitor (olaparib) in BRCA deficient ovarian cancers suggests that development of alternative synthetic lethality strategies is highly desirable. The flap structure specific endonuclease-1 (FEN1) is critical for DNA long patch base excision repair (LP-BER). FEN1 is a key player in Okazaki fragment maturation during replication, rescue of stalled replication forks and maintenance of telomeres.

Method

We evaluated FEN1 mRNA expression in breast cancer (n=2329), FEN1 protein expression in 1462 breast cancers, 140 gastric cancers and 156 epithelial ovarian cancers. A FEN1 drug discovery program has been developed and a compound library of 391,275 compounds has been screened.  We have isolated several novel FEN1 inhibitors. We have tested a prototypical FEN1 inhibitor in ovarian cancer models; A2780 (platinum sensitive), A2780cis (platinum resistant), PEO1 (BRCA2 germ-line deficient, platinum sensitive) and PEO4 (BRCA2 germ-line proficient, platinum resistant) cells.

Results

We whole exome sequenced and DNA repair expression profiled A2780, A2780cis, PEO1 and PEO4 cells to identify differential markers of platinum resistance. Interestingly, cisplatin treatment induced FEN1 expression in ovarian cancer cells. FEN1 knock down resulted in platinum sensitivity in A2780cis cells which was associated with DNA double strand break (DSB) accumulation, G2M cell cycle arrest and apoptosis. Importantly, FEN1 inhibitor treatment reversed platinum resistance in A2780cis cells and also leads to DSB accumulation, G2M cell cycle arrest and apoptosis. In BRCA2 deficient PEO1 cells, FEN1 inhibitor monotherapy induced synthetic lethality as evidence by DNA double strand break (DSB) accumulation, S-phase cell cycle arrest and apoptosis compared to BRCA2 proficient PEO4 cells. An in vivo study in tumour bearing mice is on-going.

Conclusion

FEN1 depletion results in platinum sensitization. FEN1 inhibitor treatment is a platinum sensitizor and also induces synthetic lethality in BRCA2 deficient ovarian cancer cells. We provide the first evidence that FEN1 targeting is a new strategy in ovarian cancers.