Abstract
The Fanconi anaemia (FA) pathway is an important mechanism for cellular DNA damage repair, which functions to remove toxic DNA interstrand crosslinks. This is particularly relevant in the context of ovarian and other cancers which rely extensively on interstrand cross-link generating platinum chemotherapy as standard of care treatment. These cancers often respond well to initial treatment, but reoccur with resistant disease and upregulation of DNA damage repair pathways. The FA pathway is therefore of great interest as a target for therapies that aim to improve the efficacy of platinum chemotherapies, and reverse tumour resistance to these. In this review, we discuss recent advances in understanding the mechanism of interstrand cross-link repair by the FA pathway, and the potential of the component parts as targets for therapeutic agents. We then focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors. We also consider synthetic lethality between the FA pathway and other DNA damage repair pathways as a therapeutic approach.
Highlights
The Fanconi anaemia (FA) pathway is a DNA repair pathway that identifies and removes DNA interstrand cross-links (ICLs) within cells, which occur when opposing strands of the DNA double helix are connected together, preventing their separation and restricting replication and transcription [1, 2]
We focus on the current state of play of inhibitor development, covering both the characterisation of broad spectrum inhibitors and high throughput screening approaches to identify novel small molecule inhibitors
Given its close association with the BRCA1/2 genes and homologous recombination (HR), it would be unsurprising if dynamic changes in expression with chemotherapy treatment were observed, and it is unexpected that its role in ovarian cancer chemoresistance has not already been further characterised, as mutations have been shown to sensitize sarcoma tumours to poly ADP ribose polymerase (PARP) inhibitors [132]
Summary
The Fanconi anaemia (FA) pathway is a DNA repair pathway that identifies and removes DNA interstrand cross-links (ICLs) within cells, which occur when opposing strands of the DNA double helix are connected together, preventing their separation and restricting replication and transcription [1, 2]. The E2 ligase UBE2T (FANCT) has not been linked with chemoresistance in ovarian or other cancer types and is a recently categorised FA protein [86] It is associated with ICL repair, and knockdown in amoeba has been shown to moderately sensitize them to cisplatin [87]. Given its close association with the BRCA1/2 genes and HR, it would be unsurprising if dynamic changes in expression with chemotherapy treatment were observed, and it is unexpected that its role in ovarian cancer chemoresistance has not already been further characterised, as mutations have been shown to sensitize sarcoma tumours to PARP inhibitors [132]. Broad / Mechanism Synergy with specif- of action chemotheraic py Curcumin Wortmannin
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