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.