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Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma
Katerina Politi1, Pang-Dian Fan, Ronglai Shen
1Program in Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. politik@mskcc.org
Abstract:
Seventy-five percent of lung adenocarcinomas with epidermal growth factor receptor (EGFR) mutations respond to treatment with the tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib; however, drug-resistant tumors eventually emerge. In 60% of cases, resistant tumors carry a secondary mutation in EGFR (T790M), amplification of MET, or both. Here, we describe the establishment of erlotinib resistance in lung tumors, which were induced by mutant EGFR, in transgenic mice after multiple cycles of drug treatment; we detect the T790M mutation in five out of 24 tumors or Met amplification in one out of 11 tumors in these mice. This preclinical mouse model, therefore, recapitulates the molecular changes responsible for resistance to TKIs in human tumors and holds promise for the discovery of additional mechanisms of drug resistance in lung cancer.
Insights
A new mouse model mimics drug resistance in EGFR-mutated lung cancer. This model helps identify resistance mechanisms, including T790M mutations and MET amplification, crucial for developing new lung cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Epidermal growth factor receptor (EGFR) mutations drive lung adenocarcinoma, with many tumors initially responding to tyrosine kinase inhibitors (TKIs).
- Acquired resistance to TKIs like gefitinib and erlotinib is a major clinical challenge, often mediated by secondary EGFR mutations (T790M) or MET amplification.
Purpose of the Study:
- To establish and characterize a preclinical mouse model that recapitulates erlotinib resistance in EGFR-mutated lung tumors.
- To investigate the molecular mechanisms underlying acquired resistance in this model.
Main Methods:
- Induction of erlotinib resistance in EGFR-mutant lung tumors in transgenic mice through multiple drug treatment cycles.
- Genomic analysis of resistant tumors to detect secondary EGFR mutations (T790M) and MET amplification.
Main Results:
- Successfully established erlotinib-resistant lung tumors in mice with mutant EGFR.
- Detected the T790M mutation in 5/24 resistant tumors and MET amplification in 1/11 resistant tumors, mirroring human resistance mechanisms.
Conclusions:
- The developed mouse model effectively replicates key molecular changes associated with TKI resistance in human lung cancer.
- This preclinical model is valuable for discovering novel resistance mechanisms and testing new therapeutic strategies against EGFR-mutated lung cancer.
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