Explorer Use of a genetically engineered mouse model as a preclinical tool for HER 2 breast cancer

Resistance to HER2 targeted therapies presents a major clinical problem. Although preclinical studies have identified a number of possible mechanisms clinical validation has been difficult. This most likely reflects 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 PTEN conferred de novo resistance to AZD8931, while 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-tomesenchymal 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 had retained their original epithelial morphology. The data provide a strong rationale for basing therapeutic decisions on the biology of the individual resistant tumour, which may be very different from that of the primary tumour and will be specific to individual patients.