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Br J Cancer. 2017 Jun 27;117(1):113-123. doi: 10.1038/bjc.2017.133. Epub 2017 May 23.

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

Author information

1
The CRUK Gene Function Laboratory and The Breast Cancer Now Toby Robins Breast Cancer Research Centre, The Institute of Cancer Research, London SW3 6JB, UK.
2
FACS Facility, The Institute of Cancer Research, London SW3 6JB, UK.
3
Department of Applied Biotechnology, Budapest University of Technology and Economics, Műegyetem rkp 3, Budapest H-1111, Hungary.
4
Institute of Enzymology, RCNS, Hungarian Academy of Sciences, Magyar Tudósok Str. 2, Budapest H-1117, Hungary.
5
Howard Hughes Medical Institute, Department of Biochemistry, Molecular Biology, and Biophysics, University of Minnesota, Minneapolis, Minnesota 55455, USA.

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.

PMID:
28535155
PMCID:
PMC5520199
DOI:
10.1038/bjc.2017.133
[Indexed for MEDLINE]
Free PMC Article

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