Mesquita Katia A, Ali Reem, Doherty Rachel, Toss Michael S, Miligy Islam, Alblihy Adel, Dorjsuren Dorjbal, Simeonov Anton, Jadhav Ajit, Wilson David M, Hickson Ian, Tatum Natalie J, Rakha Emad A, Madhusudan Srinivasan
Translational Oncology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG7 2RD, UK.
Department of Pathology, Division of Cancer and Stem Cells, School of Medicine, University of Nottingham Biodiscovery Institute, Nottingham NG7 2RD, UK.
Cancers (Basel). 2021 Apr 14;13(8):1866. doi: 10.3390/cancers13081866.
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.
FEN1在长片段碱基切除修复（LP-BER）、冈崎片段成熟以及挽救停滞的复制叉过程中发挥着关键作用。在一个临床队列中，FEN1过表达与侵袭性表型以及铂类化疗后无进展生存期较差相关。临床前研究表明，顺铂处理可诱导FEN1表达，且FEN1的核转位依赖于与输入蛋白β的物理相互作用。FEN1缺失、基因失活或抑制可使铂耐药卵巢癌细胞对顺铂重新敏感。BRCA2缺陷细胞在用FEN1抑制剂处理后表现出合成致死性。构建了对FEN1抑制剂耐药的PEO1R细胞，这些细胞重新激活了BRCA2并过表达关键修复蛋白POLβ和XRCC1。FEN1i处理对POLβ缺陷的卵巢癌细胞具有选择性毒性，但对XRCC1缺陷的卵巢癌细胞无毒性。对391,275种化合物进行的高通量筛选鉴定出了几种适合进一步药物开发的FEN1抑制剂。我们得出结论，FEN1是卵巢癌治疗的一个有效靶点。
