IGF axis as a target for chemoprevention/therapy in aerodigestive tract cancer.

CS23-02

Insulin-like growth factors (IGFs) affect proliferation, differentiation, apoptosis, and angiogenesis. Several studies indicate that high serum levels of IGF1 are risk factors for common human cancers. The effects of IGFs are modulated by insulin-like growth factor binding proteins (IGFBPs). It has been demonstrated that the administration of molecules that interrupt IGF action leads to impressive antineoplastic activity in in vitro and in vivo models of a variety of cancers.

Recent studies have implicated the IGF-mediated signaling pathway in the resistance to anti-epidermal growth factor receptor (EGFR) therapies, suggesting that a combinational regimen targeting both EGFR and IGFR simultaneously may yield greater anticancer activity than strategies that target a single receptor. We designed the current study to investigate the effects of blocking the IGF-1R signaling pathway, either single or in combination with anti-EGFR strategies, on non-small cell lung cancer (NSCLC) and head and neck squamous cell carcinoma (HNSCC), in which overexpression of IGF-1R and EGFR has been observed. We found that blocking IGF-1R signaling pathway with IGFBP-3, small-molecule IGF-1R-specific tyrosine kinase inhibitors, or agents targeting downstream of IGF-1R signaling pathways leads to impressive antineoplastic activity in in vitro and in vivo models of NSCLC and HNSCC cancers. In addition, we found that insulin-like growth factor-1 receptor (IGF-1R) activation interferes with the antitumor activity of EGFR TKI, including erlotinib and iressa. Treatment with erlotinib or iressa increased the levels of EGFR:IGF-1R heterodimer localized on the cell membrane, activated IGF-1R and its downstream signaling mediators, and stimulated mammalian target of rapamycin (mTOR)-mediated de novo protein synthesis of survivin in NSCLC cells. Inhibition of IGF-1R activation, suppression of mTOR-mediated protein synthesis, or knock-down of survivin expression abolished resistance to the EGFR TKIs and induced apoptosis in NSCLC cells in vitro and in vivo. These data underscore the benefits of targeting IGF-1R signalling pathway for monotherapy or for simultaneously targeting multiple growth factor receptor pathways for efficient anticancer strategies in lung and head/neck cancers.