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APOBEC3 Mutagenesis May Drive Therapy Resistance in Patients With Breast Cancer
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Key Takeaways
- APOBEC3 mutagenesis is linked to therapy resistance in breast cancer, with mutations more common in metastatic cases and associated with poor outcomes.
- APOBEC3 activity may serve as a predictive biomarker for tumor evolution and therapy resistance, detectable before treatment initiation.
APOBEC3 mutagenesis emerges as a key factor in breast cancer treatment resistance, offering new avenues for targeted therapies and predictive biomarkers.
Research suggests that apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like 3 (APOBEC3) mutagenesis may be a frequent mediator of therapy resistance in breast cancer (BC), highlighting its potential as a biomarker and target for overcoming resistance. The study data were published in Nature Genetics.1
3D visualization of breast cancer cells | Image Credit: © Jack - stock.adobe.com
BC is the most commonly diagnosed cancer in women, accounting for approximately 30% of all cancer diagnoses. Statistics predict that over 300,000 women will be diagnosed with invasive BC, according to the American Cancer Society. Of this population, over 40,000 are expected to die despite continued advancements in treatment.2
Resistance remains a significant obstacle for many patients as they progress through successive lines of therapy. This is largely due to the heterogeneity of the disease and the different mutations that underlie resistances to different types of therapies. For example, overexpression of genes such as ESR1, NF1, and HER2 can result in resistance to antiestrogens, CDK4/6 inhibitors, and PI3K inhibitors.1
In a study of 3880 samples from patients with BC, researchers identified a type of mutation linked to enzymes called APOBEC3, which help the body fight viruses but can also cause DNA changes that lead to cancer. APOBEC3—which is driven by the enzymes A3A and A3B—is responsible for inducing characteristic mutations in resistance-associated genes such as RB1, ESR1, and ARID1A. High levels of APOBEC3 have been tied to worse outcomes and resistance to tamoxifen in estrogen receptor–positive BC. These mutation patterns are more common in metastatic BC than in early-stage tumors and may help cancer adapt during hormone therapy.1,3
“We identified that 60% of APOBEC3-dominant tumors had APOBEC3 signatures at earlier stages, and 95% showed A3A or A3B protein expression, supporting the idea that APOBEC3 activity exists early on,” the researchers wrote.1
APOBEC3 activity holds promise as a predictive biomarker to identify tumors with high potential for evolution and therapy resistance because these signatures can be detected before treatment. Additionally, the study highlights 2 promising therapeutic vulnerabilities in APOBEC3-dominant tumors, including a unique dependence on the PI3K pathway and a high tumor mutational burden, which may make these cancers more responsive to immune checkpoint inhibitors.1
These insights support the potential of APOBEC3-based biomarkers to guide the use of existing therapies (eg, CDK4/6 inhibitors and antibody-drug conjugates) and the development of more targeted treatment strategies. However, limitations such as reliance on targeted panel sequencing, the predominance of ER-positive tumors, and the focus on metastatic disease underscore the need for larger, more diverse cohorts to fully understand the role of APOBEC3 mutagenesis across all BC subtypes and stages.
“The pre-existence of APOBEC3 in breast cancer establishes the potential for the development of biomarkers that can detect this underlying evolvability before exposure to therapy,” the researchers wrote. “Such biomarkers are likely to be the first step toward enabling treatment strategies that overcome resistance and limit the use of unnecessary therapies to those not at risk of such evolution.”1
