title: Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.
abstract: BACKGROUND
  Somatic mutations in the kinase domain of the epidermal growth factor receptor tyrosine kinase gene EGFR are common in lung adenocarcinoma. The presence of mutations correlates with tumor sensitivity to the EGFR inhibitors erlotinib and gefitinib, but the transforming potential of specific mutations and their relationship to drug sensitivity have not been described.
  
  
  RESULTS
  Here, we demonstrate that EGFR active site mutants are oncogenic. Mutant EGFR can transform both fibroblasts and lung epithelial cells in the absence of exogenous epidermal growth factor, as evidenced by anchorage-independent growth, focus formation, and tumor formation in immunocompromised mice. Transformation is associated with constitutive autophosphorylation of EGFR, Shc phosphorylation, and STAT pathway activation. Whereas transformation by most EGFR mutants confers on cells sensitivity to erlotinib and gefitinib, transformation by an exon 20 insertion makes cells resistant to these inhibitors but more sensitive to the irreversible inhibitor CL-387,785.
  
  
  CONCLUSIONS
  Oncogenic transformation of cells by different EGFR mutants causes differential sensitivity to gefitinib and erlotinib. Treatment of lung cancers harboring EGFR exon 20 insertions may therefore require the development of alternative kinase inhibition strategies.
authors.affiliation: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America. heidig@broad.mit.edu
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.forename: Tzu-Hsiu
authors.initials: TH
authors.lastname: Chen
authors.forename: Whei
authors.initials: W
authors.lastname: Feng
authors.forename: Pasi A
authors.initials: PA
authors.lastname: Jänne
authors.forename: James V
authors.initials: JV
authors.lastname: Alvarez
authors.forename: Mauro
authors.initials: M
authors.lastname: Zappaterra
authors.forename: Sara E
authors.initials: SE
authors.lastname: Bulmer
authors.forename: David A
authors.initials: DA
authors.lastname: Frank
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.forename: William R
authors.initials: WR
authors.lastname: Sellers
authors.forename: Matthew
authors.initials: M
authors.lastname: Meyerson
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D000069347:Erlotinib Hydrochloride; D005091:Exons; D000077156:Gefitinib; D015316:Genetic Therapy; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009154:Mutation; D041681:NIH 3T3 Cells; D009374:Neoplasms, Experimental / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011799:Quinazolines / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism; D055765:Shc Signaling Adaptor Proteins; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; D014162:Transfection; D014410:Tumor Stem Cell Assay
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000970:Antineoplastic Agents; D047428:Protein Kinase Inhibitors; D011799:Quinazolines; C528024:SHC1 protein, human; D050796:STAT3 Transcription Factor; D055765:Shc Signaling Adaptor Proteins; C528034:Shc1 protein, mouse; D000071425:Src Homology 2 Domain-Containing, Transforming Protein 1; C118029:CL 387785; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D051057:Proto-Oncogene Proteins c-akt; D000077156:Gefitinib