Dasatinib blocks cetuximab- and radiation-induced nuclear translocation of the epidermal growth factor receptor in head and neck squamous cell carcinoma

Abstract 

Background and purpose

The aberrant expression of epidermal growth factor receptor (EGFR) has been linked to the etiology of head and neck squamous cell carcinoma (HNSCC). The first major phase III trial combining cetuximab with radiation confirmed a strong survival advantage. However, both cetuximab and radiation can promote EGFR translocation to the nucleus where it enhances resistance to both of these modalities. In this report we sought to determine how to block cetuximab- and radiation-induced translocation of EGFR to the nucleus in HNSCC cell lines.

Material and methods

We utilized three established HNSCC cell lines, SCC1, SCC6 and SCC1483 and measured nuclear translocation of EGFR after treatment with cetuximab or radiation. We then utilized dasatinib (BMS-354825), a potent, orally bioavailable inhibitor of several tyrosine kinases, including the Src family kinases, to determine if SFKs blockade could abrogate cetuximab- and radiation-induced nuclear EGFR translocation.

Results

Cetuximab and radiation treatment of all three HNSCC lines lead to translocation of the EGFR to the nucleus. Blockade of SFKs abrogated cetuximab- and radiation-induced EGFR translocation to the nucleus.

Conclusions

The data presented in this report suggest that both cetuximab and radiation can promote EGFR translocation to the nucleus and dasatinib can inhibit this process. Collectively these findings may suggest that dasatinib can limit EGFR translocation to the nucleus and may enhance radiotherapy plus cetuximab in HNSCC.

Abbreviations: cEGFR, cytoplasmic epidermal growth factor receptor, CRC, colorectal cancer, DMSO, dimethyl sulfoxide, EGF, epidermal growth factor, EGFR, epidermal growth factor receptor, FBS, fetal bovine serum, FDA, food and drug administration, HNSCC, head and neck squamous cell carcinoma, mAb, monoclonal antibody, nEGFR, nuclear epidermal growth factor receptor, NSCLC, non-small cell lung cancer, PCNA, proliferating cell nuclear antigen, p-Tyr, phosphotyrosine, RTK, receptor tyrosine kinase, SCC, squamous cell carcinoma, SFK, Src family kinases, TKI, tyrosine kinase inhibitor

Keywords: EGFR, Cetuximab, Radiation, Src family kinases, Dasatinib, Head and neck cancer