Erlotinib resistance in mouse models of epidermal growth factor receptor-induced lung adenocarcinoma

SUMMARY 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.

[1]  J. Jonkers,et al.  Modeling therapy resistance in genetically engineered mouse cancer models. , 2008, Drug resistance updates : reviews and commentaries in antimicrobial and anticancer chemotherapy.

[2]  William Pao,et al.  MET amplification occurs with or without T790M mutations in EGFR mutant lung tumors with acquired resistance to gefitinib or erlotinib , 2007, Proceedings of the National Academy of Sciences.

[3]  Jos Jonkers,et al.  Selective induction of chemotherapy resistance of mammary tumors in a conditional mouse model for hereditary breast cancer , 2007, Proceedings of the National Academy of Sciences.

[4]  Joon-Oh Park,et al.  MET Amplification Leads to Gefitinib Resistance in Lung Cancer by Activating ERBB3 Signaling , 2007, Science.

[5]  H. Sasaki,et al.  PIK3CA mutation status in Japanese lung cancer patients. , 2006, Lung cancer.

[6]  P. Jänne,et al.  Allelic dilution obscures detection of a biologically significant resistance mutation in EGFR-amplified lung cancer. , 2006, The Journal of clinical investigation.

[7]  Y. Yatabe,et al.  PTEN and PIK3CA Expression Is Associated with Prolonged Survival after Gefitinib Treatment in EGFR-Mutated Lung Cancer Patients , 2006, Journal of thoracic oncology : official publication of the International Association for the Study of Lung Cancer.

[8]  P. Jänne,et al.  The impact of human EGFR kinase domain mutations on lung tumorigenesis and in vivo sensitivity to EGFR-targeted therapies. , 2006, Cancer cell.

[9]  H. Varmus,et al.  Lung adenocarcinomas induced in mice by mutant EGF receptors found in human lung cancers respond to a tyrosine kinase inhibitor or to down-regulation of the receptors. , 2006, Genes & development.

[10]  Oriol Casanovas,et al.  Drug resistance by evasion of antiangiogenic targeting of VEGF signaling in late-stage pancreatic islet tumors. , 2005, Cancer cell.

[11]  M. Meyerson,et al.  EGFR mutation and resistance of non-small-cell lung cancer to gefitinib. , 2005, The New England journal of medicine.

[12]  H. Varmus,et al.  Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain , 2005, PLoS medicine.

[13]  H. Varmus,et al.  KRAS Mutations and Primary Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib , 2005, PLoS medicine.

[14]  R. Wilson,et al.  EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[15]  S. Gabriel,et al.  EGFR Mutations in Lung Cancer: Correlation with Clinical Response to Gefitinib Therapy , 2004, Science.

[16]  Patricia L. Harris,et al.  Activating mutations in the epidermal growth factor receptor underlying responsiveness of non-small-cell lung cancer to gefitinib. , 2004, The New England journal of medicine.

[17]  H. Varmus,et al.  Induction and apoptotic regression of lung adenocarcinomas by regulation of a K-Ras transgene in the presence and absence of tumor suppressor genes. , 2001, Genes & development.

[18]  J. Tichelaar,et al.  Conditional Expression of Fibroblast Growth Factor-7 in the Developing and Mature Lung* , 2000, The Journal of Biological Chemistry.

[19]  L. Chin,et al.  Role of the INK4a Locus in Tumor Suppression and Cell Mortality , 1996, Cell.

[20]  T. Dragani,et al.  Genetics of murine lung tumors. , 1995, Advances in cancer research.

[21]  R. Weinberg,et al.  Tumor spectrum analysis in p53-mutant mice , 1994, Current Biology.