Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells

Jenni Nikkilä, Rahul Kumar, James Campbell, Inger Brandsma, Helen N. Pemberton, Fredrik Wallberg, Kinga Nagy, Ildikó Scheer, Beata G. Vertessy, Artur A. Serebrenik, Valentina Monni, Reuben S. Harris, Stephen J. Pettitt, Alan Ashworth, Christopher J. Lord

Research output: Contribution to journalArticlepeer-review

61 Scopus citations

Abstract

Background:Elevated APOBEC3B expression in tumours correlates with a kataegic pattern of localised hypermutation. We assessed the cellular phenotypes associated with high-level APOBEC3B expression and the influence of p53 status on these phenotypes using an isogenic system.Methods:We used RNA interference of p53 in cells with inducible APOBEC3B and assessed DNA damage response (DDR) biomarkers. The mutational effects of APOBEC3B were assessed using whole-genome sequencing. In vitro small-molecule inhibitor sensitivity profiling was used to identify candidate therapeutic vulnerabilities.Results:Although APOBEC3B expression increased the incorporation of genomic uracil, invoked DDR biomarkers and caused cell cycle arrest, inactivation of p53 circumvented APOBEC3B-induced cell cycle arrest without reversing the increase in genomic uracil or DDR biomarkers. The continued expression of APOBEC3B in p53-defective cells not only caused a kataegic mutational signature but also caused hypersensitivity to small-molecule DDR inhibitors (ATR, CHEK1, CHEK2, PARP, WEE1 inhibitors) as well as cisplatin/ATR inhibitor and ATR/PARP inhibitor combinations.Conclusions:Although loss of p53 might allow tumour cells to tolerate elevated APOBEC3B expression, continued expression of this enzyme might impart a number of therapeutic vulnerabilities upon tumour cells.

Original languageEnglish (US)
Pages (from-to)113-123
Number of pages11
JournalBritish Journal of Cancer
Volume117
Issue number1
DOIs
StatePublished - Jun 27 2017
Externally publishedYes

Keywords

  • APOBEC3B
  • cell cycle
  • DNA damage
  • drug sensitivity
  • mutation signature

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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