Elevated APOBEC3B expression drives a kataegic-like mutation signature and replication stress-related therapeutic vulnerabilities in p53-defective cells.
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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.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.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.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.
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Cell Cycle Proteins
Minor Histocompatibility Antigens
Gene Expression Regulation, Neoplastic
Tumor Suppressor Protein p53
Gene Knockout Techniques
Cell Cycle Checkpoints
G2 Phase Cell Cycle Checkpoints
Ataxia Telangiectasia Mutated Proteins
Checkpoint Kinase 2
Poly(ADP-ribose) Polymerase Inhibitors
Checkpoint Kinase 1
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British journal of cancer, 2017, 117 (1), pp. 113 - 123
Except where otherwise noted, this item's license is described as http://creativecommons.org/licenses/by/4.0/
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