Heterodimerization of Insulin-like Growth Factor Receptor/Epidermal Growth Factor Receptor and Induction of Survivin Expression Counteract the Antitumor Action of Erlotinib

Floriana Morgillo, Jong Kyu Woo, Edward S. Kim, Waun Ki Hong, Ho-Young Lee
2006 Cancer Research  
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
more » ... n 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 mTORmediated 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) Materials and Methods Cells, reagents, and animals. The human NSCLC cell lines H596, H226B, H226Br, H460, H1299, A549, H358, H661, and H322 were from the American Type Culture Collection (Manassas, VA) and maintained in RPMI 1640 supplemented with 10% fetal bovine serum (FBS; Life Technologies, Gaithersburg, MD) in a humidified atmosphere with 5% CO 2 . IGF and EGF were from R&D Systems (Minneapolis, MN). Erlotinib were prepared as 10 mmol/L stock solution in DMSO and stored at À20jC. LY294002
doi:10.1158/0008-5472.can-06-1684 pmid:17047074 fatcat:3eeu6aoezzecrdy3wvp3alzqam