Generation of genetically engineered mice for lung cancer with mutant EGFR

Area of Science:

• Oncology
• Genetics
• Pharmacology

Background:

• Epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) are effective against lung cancer with mutant EGFR.
• Acquired resistance to EGFR-TKIs, often due to mutations like T790M and C797S, limits treatment efficacy.
• A lack of suitable animal models hinders the development of drugs to overcome this resistance.

Purpose of the Study:

• To generate a novel transgenic mouse model for evaluating in vivo efficacy of new drugs against EGFR-TKI resistance.
• To specifically address resistance mediated by the C797S mutation in EGFR.

Main Methods:

• Generated a transgenic mouse model using Cas9-mediated homology-independent targeted integration.
• The model conditionally expresses human EGFR with resistance mutations (L858R/T790M/C797S) and firefly luciferase.
• Gene expression and lung cancer development were monitored using in vivo imaging and magnetic resonance imaging.

Main Results:

• Successfully generated a mouse model that expresses human EGFR with key resistance mutations in the lungs.
• The model allows for in vivo monitoring of gene expression and lung cancer progression.
• This model is suitable for testing novel therapeutic agents targeting C797S-mediated resistance.

Conclusions:

• The developed mouse model is a valuable tool for preclinical evaluation of drugs targeting osimertinib resistance, particularly the C797S mutation.
• This knock-in system approach can be broadly applied to study oncogenesis and develop targeted therapies for other cancers.