Abstract
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.
Highlights
The 5-year survival rate for lung cancer patients remains extremely poor (V15; ref. 1), underscoring the need for more effective treatment strategies
Somatic mutations of the Epidermal growth factor receptor (EGFR) ATP binding site have been associated with the response to the EGFR tyrosine kinase inhibitors (TKIs) in some cases [17, 18], increasing number of evidence have suggested that the presence of other pathways that mediate the resistance of cancer cells to EGFR TKI therapy [36, 37]
We have shown, to our knowledge for the first time, that erlotinib induces survival of non–small cell lung cancer (NSCLC) cells by inducing heterodimerization of EGFR/insulin-like growth factor-I receptor (IGF-IR), activating IGF-IR pathway and its downstream mediators Akt and p44/42 mitogen-activated protein kinase (MAPK), and stimulating mammalian target of rapamycin (mTOR)-mediated protein synthesis of survivin that plays a crucial role in the blocking apoptosis
Summary
The 5-year survival rate for lung cancer patients remains extremely poor (V15; ref. 1), underscoring the need for more effective treatment strategies. EGFR tyrosine kinase activity can be inhibited by antibodies against the extracellular domain of EGFR, such as cetuximab, or by small molecules that block the ATP binding site of the cytoplasmic domain, such as gefitinib (ZD1839, Iressa; AstraZeneca Pharmaceuticals, Macclesfield, United Kingdom) and erlotinib (TarcevaR; OSI Pharmaceuticals; Genentech, South San Francisco, CA). Both forms of EGFR inhibition have single-agent antitumor activity against previously treated NSCLC [3, 8,9,10]. Gefitinib, combined with standard chemotherapeutic agents and/or radiotherapy in preclinical studies, has inhibited EGFR activation, causing G1 cell cycle arrest and contributing to synergistic growth inhibition [13]
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