APOBEC3 mutagenesis drives therapy resistance in breast cancer

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Acquired genetic alterations are a primary cause of resistance to endocrine and targeted therapies in metastatic breast cancer.
• The specific biological processes driving these resistance-conferring alterations remain largely unknown.

Purpose of the Study:

• To identify the mutational processes underlying therapy resistance in metastatic breast cancer.
• To investigate the role of apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) in driving these genetic alterations and therapy resistance.

Main Methods:

• Analysis of tumor-normal sequencing data from 3,880 clinically annotated patient samples.
• Whole-genome sequencing of breast cancer models and paired primary-metastatic samples.
• Assessment of mutational signatures and their correlation with clinical outcomes and therapeutic resistance.

Main Results:

• Mutational signatures associated with APOBEC3 enzymes were frequently found and enriched in post-treatment hormone receptor-positive breast cancers.
• APOBEC3-associated signatures correlated with shorter progression-free survival in patients receiving antiestrogen plus CDK4/6 inhibitor therapy.
• Active APOBEC3 mutagenesis was shown to promote therapy resistance via alterations like RB1 loss, and evidence of APOBEC3 activity was present even in pre-treatment samples.

Conclusions:

• APOBEC3 mutagenesis is a significant mediator of therapy resistance in breast cancer.
• APOBEC3 activity plays a pervasive role in breast cancer evolution and contributes to treatment failure.
• Targeting APOBEC3 may represent a novel strategy to overcome endocrine and targeted therapy resistance in breast cancer.