Use of a genetically engineered mouse model as a preclinical tool for HER2 breast cancer
Helen Creedon1, Lucy A Balderstone1, Morwenna Muir1
1Edinburgh Cancer Research UK Centre, University of Edinburgh, Crewe Road South, Edinburgh EH4 2XR, UK.
Abstract:
Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies presents a major clinical problem. Although preclinical studies have identified a number of possible mechanisms, clinical validation has been difficult. This is most likely to reflect the reliance on cell-line models that do not recapitulate the complexity and heterogeneity seen in human tumours. Here, we show the utility of a genetically engineered mouse model of HER2-driven breast cancer (MMTV-NIC) to define mechanisms of resistance to the pan-HER family inhibitor AZD8931. Genetic manipulation of MMTV-NIC mice demonstrated that loss of phosphatase and tensin homologue (PTEN) conferred de novo resistance to AZD8931, and a tumour fragment transplantation model was established to assess mechanisms of acquired resistance. Using this approach, 50% of tumours developed resistance to AZD8931. Analysis of the resistant tumours showed two distinct patterns of resistance: tumours in which reduced membranous HER2 expression was associated with an epithelial-to-mesenchymal transition (EMT) and resistant tumours that retained HER2 expression and an epithelial morphology. The plasticity of the EMT phenotype was demonstrated upon re-implantation of resistant tumours that then showed a mixed epithelial and mesenchymal phenotype. Further AZD8931 treatment resulted in the generation of secondary resistant tumours that again had either undergone EMT or retained their original epithelial morphology. The data provide a strong rationale for basing therapeutic decisions on the biology of the individual resistant tumour, which can be very different from that of the primary tumour and will be specific to individual patients.
Insights
Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies can be overcome by understanding tumor biology. A mouse model revealed two resistance patterns: epithelial-to-mesenchymal transition (EMT) or retained HER2 expression, guiding personalized treatment strategies.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Resistance to human epidermal growth factor receptor 2 (HER2)-targeted therapies is a significant clinical challenge.
- Preclinical models often fail to capture the complexity of human tumors, hindering the validation of resistance mechanisms.
- Understanding resistance is crucial for improving treatment outcomes in HER2-driven cancers.
Purpose of the Study:
- To utilize a genetically engineered mouse model (MMTV-NIC) to investigate resistance mechanisms to the pan-HER inhibitor AZD8931.
- To identify de novo and acquired resistance pathways in HER2-driven breast cancer.
- To explore the heterogeneity and plasticity of resistance phenotypes.
Main Methods:
- A genetically engineered mouse model (MMTV-NIC) of HER2-driven breast cancer was employed.
- Genetic manipulation (PTEN loss) was used to induce de novo resistance.
- A tumor fragment transplantation model assessed acquired resistance to AZD8931.
- Resistant tumors were analyzed for changes in HER2 expression, epithelial-to-mesenchymal transition (EMT), and morphology.
Main Results:
- Loss of phosphatase and tensin homologue (PTEN) conferred de novo resistance to AZD8931.
- Acquired resistance developed in 50% of tumors treated with AZD8931.
- Two distinct resistance patterns emerged: reduced HER2 with EMT, or retained HER2 with epithelial morphology.
- The EMT phenotype demonstrated plasticity upon re-implantation, and secondary resistance showed similar patterns.
Conclusions:
- Genetically engineered mouse models are valuable for studying resistance to HER2-targeted therapies.
- Tumor resistance to AZD8931 can arise through distinct mechanisms, including EMT or HER2 retention.
- Therapeutic decisions should be guided by the specific biology of individual resistant tumors, acknowledging patient-specific heterogeneity.
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