Pharmacodynamic modelling of resistance to epidermal growth factor receptor inhibition in brain metastasis mouse models

Abstract

Purpose: Epidermal growth factor receptor (EGFR) is thought to play a role in the regulation of cell proliferation; with its activation stimulating tumour growth. EGFR inhibitors have shown promise in the treatment of cancer, particularly in non-small cell lung cancer, however, resistance is observed in the majority of patients. A tumour growth model was developed aiming to explain this resistance. Methods: The model incorporating populations of both sensitive and resistant cells were fitted to data from a study of EGFR inhibitor AZD3759 in brain metastasis mouse models. The observed regrowth of tumours in higher dose groups suggested the development of resistance to treatment. The bioluminescence observations were highly variable, covering many orders of magnitude, so to assess how reliable the model was, the parameter estimates were compared to those found in less noisy subcutaneous mouse models. Results: The fitted model suggested that resistance was mainly due to a proportion of cells being resistant at baseline, and the contribution of mutations occurring during the study leading to resistance was negligible. Estimated growth rate and dose–response was found to be comparable between brain metastasis and subcutaneous mouse models. Conclusions: The developed model to describe resistance suggests that the resistance to EGFR-inhibition seen in these xenografts is best described by assuming a small percentage of cells are resistant to treatment at baseline. This model suggests changes to dosing and dosing schedule may not prevent resistance to treatment developing, and that additional treatments would need to be used in combination to overcome resistance.