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Cell and Tumor Biology |
1 Department of Medical Oncology, Dana-Farber Cancer Institute; 2 Department of Medicine; Brigham and Women's Hospital; Departments of 3 Medicine and 4 Pathology, Harvard Medical School, Boston, MA; and 5 The Broad Institute at MIT and Harvard, Cambridge, Massachusetts
Requests for reprints: Jingrui Jiang, Dana-Farber Cancer Institute, 44 Binney Street, Mayer 534, Boston, MA 02115. Phone: 617-632-3575; Fax: 617-632-4388; E-mail: jingrui_jiang{at}dfci.harvard.edu.
Epidermal growth factor receptor (EGFR) plays critical roles in many biological processes and in tumorigenesis. Here, we show that two mutated EGFRs found in lung and other malignancies, EGFR-G719S and EGFR-L858R, could transform Ba/F3 cells to interleukin-3 (IL-3)–independent growth, in a ligand-independent manner, an activity associated with the transforming function of other mutated tyrosine kinases. The mutated receptors are autophosphorylated in the absence of IL-3 without EGF stimulation, and their expression led to the constitutive activation of signal transducers and activators of transcription 5, extracellular signal-regulated kinase 1/2 (ERK1/2), ERK5, and AKT. In wild-type EGFR-expressing Ba/F3 cells, the major EGF-mediated signaling pathways were still intact. Gefitinib inhibited the growth of mutant EGFR-transformed Ba/F3 cells. Strikingly, the gefitinib sensitivity of cells expressing the L858R mutant was significantly greater than that of cells expressing the G719S mutant form, suggesting that distinct EGFR mutations may be differentially sensitive to small-molecule inhibitors. Furthermore, our data showed an antiproliferative effect of gefitinib on the EGFR-transformed Ba/F3 cells. Our results provide a model system to study the function of mutated EGFR and the differential effects of pharmacologic EGFR inhibition on the distinct mutant forms of this tyrosine kinase.
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