APOBEC and Cancer Viroimmunotherapy: Thinking the Unthinkable.
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Embargo End Date
ICR Authors
Authors
Vile, RG
Melcher, A
Pandha, H
Harrington, KJ
Pulido, JS
Melcher, A
Pandha, H
Harrington, KJ
Pulido, JS
Document Type
Journal Article
Date
2021-06-15
Date Accepted
2021-01-19
Abstract
The apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) family protects against infection by degrading incoming viral genomes through cytosine deamination. Here, we review how the potential to unleash these potent DNA mutagens comes at a price as APOBEC DNA mutagenesis can contribute to development of multiple types of cancer. In addition, because viral infection induces its expression, APOBEC is seen as the enemy of oncolytic virotherapy through mutation of the viral genome and by generating virotherapy-resistant tumors. Therefore, overall APOBEC in cancer has received very poor press. However, we also speculate how there may be silver linings to the storm clouds (kataegis) associated with APOBEC activity. Thus, although mutagenic genomic chaos promotes emergence of ever more aggressive subclones, it also provides significant opportunity for cytotoxic and immune therapies. In particular, the superpower of cancer immunotherapy derives in part from mutation, wherein generation of tumor neoantigens-neoantigenesis-exposes tumor cells to functional T-cell repertoires, and susceptibility to immune checkpoint blockade. Moreover, APOBECs may be able to induce suprathreshold levels of cellular mutation leading to mitotic catastrophe and direct tumor cell killing. Finally, we discuss the possibility that linking predictable APOBEC-induced mutation with escape from specific frontline therapies could identify mutated molecules/pathways that can be targeted with small molecules and/or immunotherapies in a Trap and Ambush strategy. Together, these considerations lead to the counterintuitive hypothesis that, instead of attempting to expunge and excoriate APOBEC activity in cancer therapy, it might be exploited-and even, counterintuitively, encouraged.
Citation
Clinical cancer research : an official journal of the American Association for Cancer Research, 2021
Source Title
Publisher
AMER ASSOC CANCER RESEARCH
ISSN
1078-0432
eISSN
1557-3265
Research Team
Targeted Therapy
Targeted Therapy
Targeted Therapy