Bicalutamide increases phospho-Akt levels through Her2 in patients with prostate cancer

Abstract

Bicalutamide monotherapy is emerging as an alternative in the treatment of locally advanced prostate cancer. However, a significant number of these patients will recur and be in need of second-line therapies. The knowledge of molecular arrangements after pharmacological therapy seems to be a new primary prerequisite to predict the efficacy or the failure of a secondary therapy. Based on these considerations, we have conducted this study in order to analyze the expressions of phosphatase and tensin homolog deleted on chromosome 10 (PTEN), Akt, epidermal growth factor receptor (EGFR), phospho-EGFR (p-EGFR), human EGFR2 (Her2), and phospho-Her2 (p-Her2) after bicalutamide treatment. For this purpose, we evaluated retrospectively 69 prostate cancer tissues derived from patients who received radical prostatectomy as the only treatment, and 81 from patients who received bicalutamide for 120 days before surgery. In addition, we analyzed at different time points the effects of castration performed on athymic mice bearing the LuCaP 35 xenograft line at different times. We observed that bicalutamide treatment increased significantly the levels of p-Akt, EGFR, and Her2 with a concomitant reduction in PTEN. This effect was time dependent and required of sufficient time to be evident as indicated by data obtained with the LuCaP 35 tumors. A logistic multiple regression analysis revealed that a switch of p-Akt control from a PTEN/EGFR- to Her2-after bicalutamide treatment was possible. Since Akt and Her2 can be associated with reduced drug sensitivity, our report suggests that the evaluation of molecular arrangements after bicalutamide treatment could be useful to identify subsets of patients who will be molecular permissive for new adjuvant anti-target therapies.