You are here

PLoS Med DOI:10.1371/journal.pmed.0020313

Oncogenic transformation by inhibitor-sensitive and -resistant EGFR mutants.

Publication TypeJournal Article
Year of Publication2005
AuthorsGreulich, H, Chen, T-H, Feng, W, Jänne, PA, Alvarez, JV, Zappaterra, M, Bulmer, SE, Frank, DA, Hahn, WC, Sellers, WR, Meyerson, M
JournalPLoS Med
Volume2
Issue11
Pagese313
Date Published2005 Nov
ISSN1549-1676
KeywordsAdaptor Proteins, Signal Transducing, Animals, Antineoplastic Agents, Cell Transformation, Neoplastic, Drug Resistance, Neoplasm, Erlotinib Hydrochloride, Exons, Genetic Therapy, Humans, Mice, Mice, Nude, Mutation, Neoplasms, Experimental, NIH 3T3 Cells, Protein Kinase Inhibitors, Proto-Oncogene Proteins c-akt, Quinazolines, Receptor, Epidermal Growth Factor, Shc Signaling Adaptor Proteins, Src Homology 2 Domain-Containing, Transforming Protein 1, STAT3 Transcription Factor, Transfection, Tumor Stem Cell Assay
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.

METHODS AND FINDINGS: 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.

CONCLUSION: 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.

URLhttp://dx.plos.org/10.1371/journal.pmed.0020313
DOI10.1371/journal.pmed.0020313
Pubmed

http://www.ncbi.nlm.nih.gov/pubmed/16187797?dopt=Abstract

Alternate JournalPLoS Med.
PubMed ID16187797
PubMed Central IDPMC1240052