Abstract 338: Enhanced cetuximab and radiosensitization with src inhibition in head and neck cancer

Abstract

Abstract The epidermal growth factor receptor (EGFR) is a ubiquitously expressed receptor tyrosine kinase (RTK) that initiates a spectrum of signaling pathways that promote cell proliferation, differentiation, migration, motility, and metastasis. The EGFR has been strongly linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III clinical trial combining cetuximab with radiation in HNSCC confirmed a strong survival advantage for patients on the cetuximab arm. It has recently been reported, however, that cetuximab and radiation can induce EGFR to the nucleus where it can enhance resistance to both of these therapeutic modalities. In this report we sought to determine how to block cetuximab and radiation induced translocation of EGFR to the nucleus to increase the efficacy of this therapeutic regimen in HNSCC. We utilized three established HNSCC lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of the EGFR after treatment with cetuximab, radiation or the combination. Both cetuximab and radiation treatment could induce nuclear translocation of the EGFR in all SCC lines tested. Strikingly, time course analysis indicated that cetuximab could stimulate movement of the EGFR to the nucleus within one hour where it maintained its present for greater than 96 hours. Conversely, radiation could stimulate EGFR translocation to the nucleus within 0.5 hours, but returned to baseline levels within four hours. Both cetuximab and radiation treatment of SCC lines led to the phosphorylation of tyrosine 845 (Y845) of the EGFR. Y845 is phosphorylated specifically by the non-receptor tyrosine kinase Src and/or its family of kinases (SFKs). Blockade of SFKs by dasatinib could abrogate cetuximab and radiation induced EGFR translocation to the nucleus indicating that SFKs are crucial for the movement of the EGFR to the nucleus. In addition, pre-treatment of HNSCC cells with dasatinib, followed by cetuximab and radiation enhanced the suppression of ERK activity in all three SCC cell lines. Furthermore, combining dasatinib with cetuximab/radiation treatment exhibited additive inhibitory effects on cell growth or clonogenic formation. These data suggest that both cetuximab and radiation can induce EGFR to the nucleus and blockade of SFKs using dasatinib can abrogate this translocation. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 338.