Generation of genetically engineered mice for lung cancer with mutant EGFR

Abstract

Although epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) have shown dramatic response and improvement in treating lung cancer with mutant EGFR, the emergence of drug resistance remains a major problem. In particular, some mutations including T790 M and C797S have been recognized as mechanisms of acquired resistance because they weaken binding affinity to drugs. To date, many attempts have been made to develop a new drug for overcoming acquired resistance to EGFR-TKIs, including secondary mutations. However, an appropriate animal model to evaluate in vivo efficacy during novel drug development remains lacking. In this study, we generated a novel transgenic mouse model that conditionally expresses human EGFR^{L858R/T790M/C797S} and firefly luciferase using Cas9-mediated homology-independent targeted integration. Using a lung-specific Sftpc-CreER^T2 mouse line, we induced expression of both the human EGFR^{L858R/T790M/C797S} transgene and firefly luciferase in the lungs of adult mice. The expression of these genes and lung cancer occurrence was monitored using an in vivo imaging system and magnetic resonance imaging, respectively. Overall, our mouse model can be utilized to develop new drugs for overcoming C797S-mediated resistance to osimertinib; further, such knock-in systems for expressing oncogenes may be applied to study tumorigenesis and the development of other targeted agents.

Keywords: C797S; Epidermal growth factor receptor (EGFR); Genetically engineered mice (GEM); Mutant EGFR; Osimertinib; Resistance.