Interaction of EGFR and IGF-1R signals to modulate the anti-proliferative and biochemical responses of head and neck squamous cancer (HNSCC) cells to EGFR inhibitors

Abstract

6045 Background: Epidermal growth factor receptor (EGFR) inhibitors improve the efficacy of radiotherapy for HNSCC and as single-agents induce tumor responses or stabilization in a minority of patients. The molecular mechanisms that dictate the spectrum of observed responses are not well understood. Methods/Results: Exposure of the HNSCC lines SCC-9 and SCC-25 in vitro to the EGFR inhibitors PD158780, lapitinib, or cetuximab suppressed cell proliferation and cell cycle progression into S-phase. Immunoblots showed that PD158780 inhibited autocrine activation of the EGFR, reduced phosphorylation of the downstream signaling proteins AKT and Erk, and affected cell cycle regulatory molecules (reduced Rb phosphorylation, decreased cyclin D1 levels, and induced p27kip1). However, stimulation of the cells with an insulin-like growth factor-1 (IGF-1) analog produced a dose-dependent resistance to the anti-proliferative effects of the EGFR inhibitors. The resistance of SCC-25 cells correlated with IGF-1-induced maintenance of AKT and Rb phosphorylation and cyclin D1 expression. Conversely, the EGFRs also acted downstream of the activated IGF-1 receptors as concomitant EGFR inhibition dampened the proliferative response of the cells, reduced Erk phosphorylation and increased p27kip1 expression. Experiments with the metalloproteinase inhibitor TAPI-2 suggested that the IGF-1 activates the EGFRs through proteolytic cleavage of precursor forms of EGFR ligands. Conclusions: The proliferative and biochemical responses of HNSCC cells to EGFR inhibitors are influenced by cross-talk between the EGFR and IGF-1 receptors. One implication of this work is that the clinical response of HNSCCs to EGFR inhibitors may depend on the relative contribution of autocrine EGFR signaling to activation of specific downstream growth factor signaling pathways, whether or not these receptors are the primary or secondary source of these signals. No significant financial relationships to disclose.