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Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer

Nature Genetics volume 54, pages 1599–1608 (2022)Cite this article

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Abstract

Mutational signatures associated with apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC)3 cytosine deaminase activity have been found in over half of cancer types, including some therapy-resistant and metastatic tumors. Driver mutations can occur in APOBEC3-favored sequence contexts, suggesting that mutagenesis by APOBEC3 enzymes may drive cancer evolution. The APOBEC3-mediated signatures are often detected in subclonal branches of tumor phylogenies and are acquired in cancer cell lines over long periods of time, indicating that APOBEC3 mutagenesis can be ongoing in cancer. Collectively, these and other observations have led to the proposal that APOBEC3 mutagenesis represents a disease-modifying process that could be inhibited to limit tumor heterogeneity, metastasis and drug resistance. However, critical aspects of APOBEC3 biology in cancer and in healthy tissues have not been clearly defined, limiting well-grounded predictions regarding the benefits of inhibiting APOBEC3 mutagenesis in different settings in cancer. We discuss the relevant mechanistic gaps and strategies to address them to investigate whether inhibiting APOBEC3 mutagenesis may confer clinical benefits in cancer.

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Fig. 1: APOBEC3 mutagenesis is predicted to be a disease-modifying process in cancer that may be exploited therapeutically.
Fig. 2: Surrogate readouts of active mutagenesis by individual APOBEC3 enzymes.
Fig. 3: Addressing impact of APOBEC3 enzymes on cancer evolution.

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Acknowledgements

M.P.’s research was supported by the European Molecular Biology Organization Long-Term Fellowship (ALTF 760–2019) and is supported by the National Cancer Institute (NCI) (CA270102). J.M.’s laboratory is supported by the NCI (CA212290, CA008748, CA261183, CA270102), the Pew Charitable Trusts, the V Foundation, the Starr Cancer Consortium, the Emerald Foundation and the Geoffrey Beene and Ludwig Centers at the MSKCC. A.M.G.’s laboratory is supported by the NCI (K08CA21299), the Department of Defense (CA2000867), the American Cancer Society, the Cancer Research Foundation and the Children’s Discovery Institute. Research on APOBEC enzymes in the laboratory of M.D.W. was supported by grants from the National Institutes of Health (CA181259 and CA185799). We thank M. O’Reilly and E. Berg from the Broad Institute’s Pattern team for figure graphics.

Author information

Author notes

  1. These authors contributed equally: Mia Petljak, Abby M. Green, John Maciejowski, Matthew D. Weitzman.

Authors and Affiliations

  1. Broad Institute of MIT and Harvard, Cambridge, MA, USA

    Mia Petljak

  2. Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA

    Abby M. Green

  3. Center for Genome Integrity, Siteman Cancer Center, Washington University School of Medicine, St. Louis, MO, USA

    Abby M. Green

  4. Molecular Biology Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY, USA

    John Maciejowski

  5. Department of Pathology and Laboratory Medicine, Children’s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA

    Matthew D. Weitzman

  6. Perelman School of Medicine, Epigenetics Institute, University of Pennsylvania, Philadelphia, PA, USA

    Matthew D. Weitzman

  7. Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, Philadelphia, PA, USA

    Matthew D. Weitzman

Authors
  1. Mia Petljak
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  2. Abby M. Green
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  3. John Maciejowski
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  4. Matthew D. Weitzman
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Contributions

All authors contributed to the writing of the paper.

Corresponding author

Correspondence to Mia Petljak.

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Competing interests

M.P. is a shareholder in Vertex Pharmaceuticals and a compensated consultant through GLG Network. J.M. has received consulting fees from Ono Pharmaceutical. J.M.’s spouse is an employee of and has equity in Bristol Myers Squibb. M.P. and J.M. are inventors of the patent application entitled ‘Tracking APOBEC mutational signatures in tumor cells’ (patent pending). The remaining authors declare no competing interests.

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Nature Genetics thanks Tim Fenton, Andre Nussenzweig, and Vladimir Seplyarskiy for their contribution to the peer review of this work.

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Petljak, M., Green, A.M., Maciejowski, J. et al. Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer. Nat Genet 54, 1599–1608 (2022). https://doi.org/10.1038/s41588-022-01196-8

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