Insulin-like growth factor receptor signaling pathways and resistance to tarceva (erlotinib) in non-small cell lung cancer cells

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Purpose: The Epidermal Growth Factor Receptor (EGFR) is an important target for anticancer therapy. However, not all NSCLC cells respond to treatment with EGFR inhibitors, and the mechanism of resistance to EGFR inhibitors is poorly understood. Therefore, we studied the molecular mechanism that interferes with the activities of tarceva (Erlotinib), a selective EGFR tyrosin kinase inhibitor that has shown antitumor activities in patients with NSCLC as second / third line therapy. Methods: The effects of tarceva and its combination with inhibitors of IGF-1R signaling components on proliferation and apoptosis were assessed in a subset of NSCLC cell lines in vitro and in vivo, by using the MTT assay, anchorage-independent growth assay in soft agar, clonogenic survival assay, a flow cytometry-based TUNEL assay, western blot analyses, and a NSCLC xenograft tumor model. Results: Tarceva treatment exhibited an activation of IGF-IR signaling components, such as IGF-1R, Akt, and MAPK, in the resistant NSCLC cell lines, but not in the sensitive cell lines. Dual targeting of EGFR and IGF-1R signaling pathways through combined treatment of tarceva and inhibitors of upstream and downstream of IGF-1R signaling components showed enhanced antiproliferative activities in NSCLC cells in vitro and in vivo. Conclusion: The combination of tarceva and inhibitors of IGF-1R signaling components induced enhanced antiproliferative activities in NSCLC cells via increased apoptosis in vitro and in vivo. These results suggest that activation of IGF-1R signaling pathway confer resistance to tarceva treatment in NSCLC cells, and that simultaneous treatment with inhibitors of IGF-1R and EGFR signaling pathways might be an effective therapeutic strategy against NSCLC. Supported in part by the DAMD17-01-1-0689 from the Department of Defense (to W. K. Hong); W81XWH-04-1-0142-01-VITAL from the Department of Defense (to W. K. Hong); National Institutes of Health Grants R01 CA109520-01 (to H-Y. Lee) and CA100816-01A1 (to H-Y. Lee), National American Cancer Society, RSG-04-082-01-TBE 01(to H-Y. Lee)