Inhibitors of the Fanconi anaemia pathway as potential antitumour agents for ovarian cancer

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.

Keywords: DNA repair; Fanconi anaemia protein; carboplatin; cisplatin; inhibitors; ovarian cancer.

Figure 1.

Repair of ICLs by the FA pathway. (A) ICLs are induced by platinum chemotherapy or other agents; (B) ICLs are recognised by converging replication forks. CMG helix is polyubiquitylated by TRAIP and removed by the BARD1/BRCA2 complex, allowing access to the ICL site; (C) the FANCD2/I heterodimer is recruited to chromatin and each subunit is monoubiquitylated by the FA core complex; (D) monoubiquitylated FANCD2/I recruits endonucleases, which create incisions in one DNA strand around the ICL site, unhooking the strands and generating a DSB; (E) insertion of a single nucleotide opposite the ICL by TLS polymerases, followed by strand extension by POLζ restores one DNA duplex; (F) the intact DNA duplex is used as a template for HR repair of the DSB. RAD51 is loaded on to chromatin by BRCA1/2/PALB2 complex and multimerizes with RAD51 paralogues to form protein nucleofilaments, enabling strand exchange and template directed extension; (G) intact DNA duplexes are restored. The bound ICL adduct is no longer a toxic block to replication and can be removed by NER. Figure created using Biorender

Figure 2.

Monoubiquitylation of FANCD2/I by the FA core complex. The AG20 subcomplex (pink) is responsible for the translocation of the core complex to the nucleus. FANCM and FAAP24 associate to form a subcomplex (orange) anchoring the FA core complex to DNA at ICL sites. A central asymmetrical dimer of BL100 catalytic subcomplexes (purple) acts as an essential scaffold for the other subunits, and contains two FANCL molecules with distinct conformations. The FANCD2/I heterodimer (light blue) is bound by the FANCC/E/F subcomplex (green) and is monoubiquitylated by the E2 ubiquitin ligase UBE2T (dark blue) and corresponding E3 ligase FANCL via dynamic changes in the core complex conformation. On completion of ICL repair, the FANCD2/I heterodimer is deubiquitylated by the USP1/UAF heterodimer and dissociates from DNA. Figure created using Biorender