BACKGROUND. Erlotinib is a small-molecule tyrosine kinase inhibitor targeted EGFR, known to be overexpressed in a variety of cancers, including prostate cancer. Clinical trials showed insignificant clinical benefit in patients with castration resistant prostate cancer both when EGFR inhibitors were administered as monotherapy or in association with antiandrogens or chemotherapeutics. Why, differently to other tumors, have EGFR inhibitors been so ineffective in human prostate cancer? This is the question that we have set in this report. METHODS. For this purpose, the effectiveness of erlotinib, a selective EGFR inhibitor, in a wide range of prostate cancer cells (wild type or engineered to overexpress peculiar proteins including androgen receptor and PTEN). RESULTS. We demonstrated that the effectiveness of erlotinib was inversely correlated to the EGFR/Her2 ratio rather than EGFR/p-EGFR or Her2/p-Her2 levels. Chronic treatment with bicalutamide induced overexpression of Her2 and reduction of EGFR/Her2ratio and this was associated with increased Akt and Erk activity. In these conditions of treatment a reduced efficacy of erlotinib was observed. At the same time, an increased efficacy versus erlotinib was documented in cancer cells chronically exposed to DHT. In these culture conditions low levels of Her2 and increased EGFR/Her2 ratio were evidenced. CONCLUSIONS. Taken together, our results seem to suggest that a low EGFR/Her2 ratio and PTEN absence are the main factors responsible of erlotinib inefficacy. Therefore the inhibition of EGFR could have important antitumor effects in hormone-naive rather than in hormonally treated patients. Prostate 69: 1529-1537, 2009. (C) 2009 Wiley-Liss, Inc.
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|Titolo:||Effects of EGFR Tyrosine Kinase Inhibitor Erlotinib in Prostate Cancer Cells In Vitro|
|Data di pubblicazione:||2009|
|Appartiene alla tipologia:||01a Articolo in rivista|