Cell Transformation, Neoplastic
Mutations in the Epidermal Growth Factor Receptor (EGFR) are found in 10-20% of lung adenocarcinomas (a subtype of lung cancer). These mutations are most common in tumors in never-smokers and are associated with sensitivity to drugs that specifically block the activity of the mutant receptor. Patients with EGFR mutant tumors initially respond to treatment with these drugs, however drug-resistant disease almost invariably emerges within a year of starting treatment. In our laboratory we use genetically engineered mouse models of EGFR mutant lung cancer to study: 1) how the mutant receptors alter signaling pathways in lung cells to cause cancer and, 2) mechanisms of resistance to therapies directed against mutant EGFR.
- Politi K, Fan PD, Shen R, Zakowski M and Varmus H. Erlotinib Resistance in Mouse Models of EGFR-Induced Lung Adenocarcinoma Resembles Drug Resistance in the Human Disease. Dis Model Mech. 2010 Jan-Feb;3(1-2):111-9. Epub 2009 Dec 9. PMCID: 2806903
- Regales L, Gong Y, Shen R, De Stanchina E, Vivanco I, Goel A, Koutcher J, Spassova M, Oerfelli O, Mellingohoff I, Zakowski M, Politi K and Pao W. Dual targeting of EGFR can overcome a major drug resistance mutation in mouse models of EGFR mutant lung cancer.J Clin Invest. 2009 Oct;119(10):3000-10. doi: 10.1172/JCI38746. Epub 2009 Sep 14.PMCID: PMC2752070
- Regales L, Balak MN, Gong Y, Politi K, Sawai A, Le C, Koutcher JA, Solit DB, Rosen N, Zakowski MF, Pao W. Development of new mouse lung tumor models expressing EGFR T790M mutants associated with clinical resistance to kinase inhibitors. PLoS ONE. 2007 Aug 29;2(8):e810.PMCID: 1950079
- Politi K, Zakowski MF, Fan PD, Schonfeld EA, Pao W, Varmus HE. 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. Genes Dev. 2006 Jun 1;
- Pao W, Miller VA, Politi KA, Riely GJ, Somwar R, Zakowski MF, Kris MG, Varmus H. Acquired Resistance of Lung Adenocarcinomas to Gefitinib or Erlotinib Is Associated with a Second Mutation in the EGFR Kinase Domain. PLoS Med. 2005 Mar;2(3):e73. Epub 2005 F
- Pao W, Miller V, Zakowski M, Doherty J, Politi K, Sarkaria I, Singh B, Heelan R, Rusch V, Fulton L, Mardis E, Kupfer D, Wilson R, Kris M, Varmus H. EGF receptor gene mutations are common in lung cancers from "never smokers" and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci U S A. 2004 Sep 7;101(36):13306-11. Epub 2004 Aug 25.PMCID: 516528