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CD73 Promotes Resistance to HER2/ErbB2 Antibody Therapy
Martin Turcotte1,2,3, David Allard1,2,3, Deepak Mittal4,5
1Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Québec, Canada.
Cancer Research
|September 1, 2017
Summary
CD73 expression in cancer suppresses immune responses and hinders trastuzumab effectiveness against HER2-positive breast cancer. Targeting CD73 can improve anti-HER2 therapy outcomes.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- CD73 (ectonucleotidase) expression on tumor, stromal, and immune cells promotes immune suppression in cancer.
- The anti-HER2/ErbB2 monoclonal antibody (mAb) trastuzumab is a key therapy for HER2-positive breast cancer.
- Understanding resistance mechanisms to trastuzumab is crucial for improving patient outcomes.
Purpose of the Study:
- To investigate the role of CD73 in mediating resistance to trastuzumab therapy in HER2/ErbB2-driven breast cancer.
- To explore the regulatory pathways associated with CD73 expression in breast cancer.
- To evaluate the therapeutic potential of combining anti-CD73 mAb with anti-HER2 mAb.
Main Methods:
- Analysis of a phase III clinical trial dataset correlating CD73 gene expression with clinical outcomes of trastuzumab treatment.
- Utilizing immunocompetent mouse models of HER2/ErbB2-driven breast cancer to assess the impact of CD73 on anti-HER2 mAb efficacy.
- Employing gene ontology enrichment analysis and in vitro experiments with human mammary cells to identify CD73 regulatory pathways.
Main Results:
- High CD73 gene expression correlated significantly with poor clinical outcome in patients treated with trastuzumab.
- CD73 expression by tumor and host cells suppressed immune responses mediated by anti-HER2 mAb in mouse models.
- Combined anti-CD73 mAb and anti-HER2 mAb therapy enhanced anti-tumor activity against established tumors and metastases.
- CD73 expression was positively associated with extracellular matrix organization, TGFβ, EMT transcription factors, and HIF-1 gene signatures.
Conclusions:
- CD73 plays a significant role in mediating resistance to trastuzumab therapy in HER2/ErbB2-driven breast cancer.
- CD73 expression is regulated by pathways including TGFβ signaling and epithelial-to-mesenchymal transition (EMT).
- Targeting CD73 in combination with trastuzumab represents a promising strategy to overcome treatment resistance and improve therapeutic efficacy.
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