HER2/neu as a New Therapeutic Target of Sinonasal Undifferentiated Carcinoma

Background: Sinonasal undifferentiated carcinoma (SNUC) is a rare, highly aggressive cancer that arises in the nasal cavity and paranasal sinuses. Despite aggressive multimodal therapy, the prognosis remains poor, and the median survival time is less than 18 months. To better understand the biological features of SNUC and help develop new therapies, we examined the potential for HER2 tyrosine kinase receptor targeting for this disease.

Materials and Methods: The MDA8788-6 cell line established from a patient with T4N0M0 SNUC of the right maxillary sinus was used in this study. Phosphorylation and expression levels of tyrosine kinase receptors and several protein kinases were evaluated by Western blot analysis. Cell growth inhibition was assessed by MTT and clonogenic survival assays.

Results: Both the surgical specimen from the SNUC patient and the MDA8788-6 cell line showed overexpression and phosphorylation of HER2/neu, but did not express EGFR or c-Kit. When exposed to lapatinib, a dual inhibitor EGFR/HER2, the SNUC cell line, showed growth suppression at clinically relevant therapeutic doses (GI50∼0.5 µM by MTT assay). Western blotting revealed that lapatinib dephosphorylated HER2 in both dose- and time-dependent experiments. The downstream PI3K/AKT and MAP/ERK pathways were also downregulated by this inhibitor. PARP cleavage suggested that the mechanism of the cell growth suppression by lapatinib may be due in part to activation of pro-apoptotic pathways.

Conclusions: Phosphorylation of HER2/neu and its downstream pathways was effectively inhibited by lapatinib in our SNUC cell line. This inhibitor also successfully suppressed the cell growth of the SNUC cells at a low dose. This is the first report of molecular targeted therapy in SNUC and may be a promising avenue for novel therapies in this deadly disease.