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Updated: Aug 24, 2025

Establishing Cell Lines Overexpressing DR3 to Assess the Apoptotic Response to Anti-mitotic Therapeutics
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Addressing the benefits of inhibiting APOBEC3-dependent mutagenesis in cancer

Mia Petljak1, Abby M Green2,3, John Maciejowski4

  • 1Broad Institute of MIT and Harvard, Cambridge, MA, USA. mpetljak@broadinstitute.org.

Nature Genetics
|October 25, 2022
PubMed

Insights

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) activity drives cancer evolution and resistance. Further research is needed to define APOBEC3

Area of Science:

  • Cancer Biology
  • Genetics
  • Molecular Oncology

Background:

  • Mutational signatures linked to apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) cytosine deaminase activity are prevalent in numerous cancer types.
  • These signatures are observed in therapy-resistant and metastatic tumors, suggesting APOBEC3's role in cancer progression and treatment failure.

Purpose of the Study:

  • To investigate the role of APOBEC3 mutagenesis in driving cancer evolution, heterogeneity, metastasis, and drug resistance.
  • To identify critical knowledge gaps in APOBEC3 biology within cancer and healthy tissues to inform potential therapeutic strategies.

Main Methods:

  • Analysis of mutational signatures in various cancer types.
  • Examination of APOBEC3-favored sequence contexts in driver mutations.
  • Investigation of APOBEC3 signature distribution in tumor phylogenies and cancer cell lines.

Main Results:

  • APOBEC3-mediated mutational signatures are found in over half of cancer types, often within subclonal branches and acquired over time.
  • APOBEC3 mutagenesis is proposed as a disease-modifying process contributing to tumor heterogeneity, metastasis, and drug resistance.

Conclusions:

  • APOBEC3 mutagenesis is an ongoing process that can drive cancer evolution and resistance.
  • Defining APOBEC3's precise role and biological context is crucial for predicting the clinical benefits of its inhibition.

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