Cancer-associated FBXW7 loss is synthetic lethal with pharmacological targeting of CDC7

Mol Oncol. 2024 Feb;18(2):369-385. doi: 10.1002/1878-0261.13537. Epub 2023 Oct 22.

Abstract

The F-box and WD repeat domain containing 7 (FBXW7) tumour suppressor gene encodes a substrate-recognition subunit of Skp, cullin, F-box (SCF)-containing complexes. The tumour-suppressive role of FBXW7 is ascribed to its ability to drive ubiquitination and degradation of oncoproteins. Despite this molecular understanding, therapeutic approaches that target defective FBXW7 have not been identified. Using genome-wide clustered regularly interspaced short palindromic repeats (CRISPR)-Cas9 screens, focussed RNA-interference screens and whole and phospho-proteome mass spectrometry profiling in multiple FBXW7 wild-type and defective isogenic cell lines, we identified a number of FBXW7 synthetic lethal targets, including proteins involved in the response to replication fork stress and proteins involved in replication origin firing, such as cell division cycle 7-related protein kinase (CDC7) and its substrate, DNA replication complex GINS protein SLD5 (GINS4). The CDC7 synthetic lethal effect was confirmed using small-molecule inhibitors. Mechanistically, FBXW7/CDC7 synthetic lethality is dependent upon the replication factor telomere-associated protein RIF1 (RIF1), with RIF1 silencing reversing the FBXW7-selective effects of CDC7 inhibition. The delineation of FBXW7 synthetic lethal effects we describe here could serve as the starting point for subsequent drug discovery and/or development in this area.

Keywords: CDC7; CRISPR screen; FBXW7; cancer; synthetic lethality.

MeSH terms

  • Cell Cycle Proteins* / genetics
  • Cell Cycle Proteins* / metabolism
  • Cell Line, Tumor
  • Chromosomal Proteins, Non-Histone / genetics
  • F-Box-WD Repeat-Containing Protein 7 / genetics
  • Humans
  • Neoplasms* / genetics
  • Protein Domains
  • Protein Serine-Threonine Kinases / metabolism
  • RNA Interference
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination

Substances

  • F-Box-WD Repeat-Containing Protein 7
  • Cell Cycle Proteins
  • Ubiquitin-Protein Ligases
  • CDC7 protein, human
  • Protein Serine-Threonine Kinases
  • FBXW7 protein, human
  • GINS4 protein, human
  • Chromosomal Proteins, Non-Histone