APOBEC3-mediated therapy resistance and immunogenicity in solid tumors: from genomic scars to therapeutic vulnerabilities.

Abstract

The APOBEC3 family of cytidine deaminases, originally evolved for antiviral defense, functions as a potent source of somatic mutations in human malignancies. Although the genomic footprints of APOBEC3 were deciphered over a decade ago with characteristic mutational signatures (single-base substitution [SBS]2 and SBS13), their clinical significance is only now becoming apparent, shifting from a descriptive hallmark of mutagenesis to a potential predictor of therapy outcomes. Emerging evidence from landmark studies reveals that apolipoprotein B mRNA editing enzyme, catalytic polypeptide-like (APOBEC)-associated mutational signatures are associated with acquired resistance to targeted therapies and are an emerging biomarker of response to immune checkpoint inhibitors (ICIs). Mechanistically, therapy-induced activation of APOBEC3A and APOBEC3B drives the evolution of drug-tolerant persister cells and generates genomic diversity from which resistant clones emerge-a phenomenon demonstrated across epidermal growth factor receptor inhibitor resistance in lung cancer, endocrine therapy resistance in breast cancer, and androgen receptor blockade resistance in prostate cancer. Concurrently, studies have shown that APOBEC mutational signatures are associated with ICI benefit, including in tumor mutational burden-adjusted analyses, most notably in urothelial carcinoma and non-small-cell lung cancer. In this study, we review this emerging paradigm, focusing on the newly established mechanisms and clinical findings. We further address the translational hurdles of detecting APOBEC mutational signatures in clinical practice and emerging therapeutic strategies, including oligonucleotide-based inhibitors and synthetic lethality. Finally, we discuss standardizing APOBEC mutational signature detection for clinical use, including developing liquid biopsy-based dynamic monitoring, and designing prospective trials with APOBEC mutational signature-based stratification.

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