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Experimental Therapeutics, Molecular Targets, and Chemical Biology |
Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas
Requests for reprints: Ho-Young Lee, Department of Thoracic/Head and Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Box 432, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-6363; Fax: 713-792-0430; E-mail: hlee{at}mdanderson.org.
Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have been used to treat non–small cell lung cancer (NSCLC). However, the overall response rate to EGFR TKIs is limited, and the mechanisms mediating resistance to the drugs are poorly understood. Here, we report that insulin-like growth factor-I receptor (IGF-IR) activation interferes with the antitumor activity of erlotinib, an EGFR TKI. Treatment with erlotinib increased the levels of EGFR/IGF-IR heterodimer localized on cell membrane, activated IGF-IR and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)–mediated de novo protein synthesis of EGFR and survivin in NSCLC cells. Inhibition of IGF-IR activation, suppression of mTOR-mediated protein synthesis, or knockdown of survivin expression abolished resistance to erlotinib and induced apoptosis in NSCLC cells in vitro and in vivo. Our data suggest that enhanced synthesis of survivin protein mediated by the IGFR/EGFR heterodimer counteracts the antitumor action of erlotinib, indicating the needs of integration of IGF-IR–targeted agents to the treatment regimens with EGFR TKI for patients with lung cancer. (Cancer Res 2006; 66(20): 10100-11)
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 S. H. Oh, Q. Jin, E. S. Kim, F. R. Khuri, and H.-Y. Lee Insulin-like Growth Factor-I Receptor Signaling Pathway Induces Resistance to the Apoptotic Activities of SCH66336 (Lonafarnib) through Akt/Mammalian Target of Rapamycin-Mediated Increases in Survivin Expression Clin. Cancer Res., March 1, 2008; 14(5): 1581 - 1589. [Abstract] [Full Text] [PDF]
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F. Morgillo, W.-Y. Kim, E. S. Kim, F. Ciardiello, W. K. Hong, and H.-Y. Lee Implication of the Insulin-like Growth Factor-IR Pathway in the Resistance of Non small Cell Lung Cancer Cells to Treatment with Gefitinib Clin. Cancer Res., May 1, 2007; 13(9): 2795 - 2803. [Abstract] [Full Text] [PDF]
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