Signaling pathways in adenoid cystic cancers: implications for treatment.

Adenoid cystic cancers (ACC) in the head and neck are rare yet present a clinical dilemma. Although 5-y survivals are excellent, they have a propensity for late recurrences. Most of these cancers are initially treated with surgery followed by radiation. When recurrences happen, treatment options are limited both by the morbidity and low efficacy of re-irradiation and repeated surgical resection. Reported response rates to chemotherapy are low and targeted therapies may be one option. We, therefore, investigated signaling pathways that may be active in adenoid cystic cancers. Tissues from the last nine ACC patients resected at the University of Iowa were immunohistochemically stained with antibodies for EGFR, phosphorylated (P) Akt, and P-MAPK in order to molecularly characterize these tumors. An ACC cell line (ACC3) was also characterized by western blot. We found that seven of the nine tumor samples had strong expression of P-Akt and 5/9 had P-MAPK. None of them had EGFR expression. In the ACC3 cell line, similar data was found in that there was P-Akt and P-MAPK but no EGFR expression. We tested the HIV protease inhibitor nelfinavir (NFV) which has been shown to inhibit Akt signaling to see its effect on ACC3 cells. Both P-Akt and P-MAPK were inhibited with NFV in ACC3 cells and this resulted in growth inhibition and clonogenic death. In patients where re-irradiation or further surgery is not an option, a trial of NFV may be warranted.