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Updated: Feb 7, 2026
Studying the Stoichiometry of Epidermal Growth Factor Receptor in Intact Cells using Correlative Microscopy
Published on: September 11, 2015
Pharmacodynamic modelling of resistance to epidermal growth factor receptor inhibition in brain metastasis mouse
Emma C Martin1, Leon Aarons2, James W T Yates3
1Centre for Applied Pharmacokinetic Research, Manchester Pharmacy School, The University of Manchester, Manchester, UK. emma.martin@leicester.ac.uk.
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.
Insights
Tumour resistance to epidermal growth factor receptor (EGFR) inhibitors in cancer may stem from a small fraction of pre-existing resistant cells, not new mutations. This suggests combination therapies are needed to overcome EGFR inhibitor resistance.
Area of Science:
- Oncology
- Cancer Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) signaling drives tumor growth, making EGFR inhibitors a key cancer therapy.
- Resistance to EGFR inhibitors is common, limiting treatment efficacy, especially in non-small cell lung cancer.
Purpose of the Study:
- To develop and validate a tumor growth model that explains observed resistance to EGFR inhibitors.
- To investigate the mechanisms underlying resistance to EGFR inhibition in preclinical cancer models.
Main Methods:
- A mathematical model incorporating both sensitive and resistant cell populations was developed.
- The model was fitted to bioluminescence data from AZD3759 EGFR inhibitor treatment in brain metastasis mouse models.
- Model parameter estimates were compared with those from subcutaneous mouse models to assess reliability.
Main Results:
- The model indicated that tumor resistance primarily arises from a baseline proportion of resistant cells.
- The contribution of acquired mutations to resistance during treatment was found to be negligible.
- Growth rates and dose-response relationships were consistent between brain metastasis and subcutaneous models.
Conclusions:
- Tumor resistance to EGFR inhibitors in xenografts is best explained by pre-existing resistant cell populations.
- Modifying dosing or schedules alone may not prevent resistance; combination therapies are likely necessary.
- The findings highlight the importance of targeting resistant cell populations to improve cancer treatment outcomes.
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