title: Gefitinib and bicalutamide show synergistic effects in primary cultures of prostate cancer derived from androgen-dependent naive patients.
abstract: We previously demonstrated that the inhibition of the epidermal growth factor receptor (EGFR) signalling affects the endocrine therapy responses of prostate cancer (PCa) cells and that bicalutamide (BCLT) is able to reinforce PI3K activity through mechanisms involving PTEN decrement and EGFR and Her2 activities. The aim of this study was to evaluate if the hormonal therapy with BCLT can affect the EGFR-targeted therapy using primary cultures obtained from 22 human PCa tissues harvested after radical prostatectomy (RP) in patients who received (n=10) BCLT and those that did not (n=12) as neoadjuvant hormone therapy (NHT). We demonstrated that cultures derived from PCa tissues harvested after NHT presented significantly higher EGFR and Her2 levels compared to cultures derived from control patients. However, cultures derived from patients with NHT were less sensitive to gefitinib when compared to cultures derived from control patients. Conversely, BCLT effectiveness did not seem to be different in the two groups and was partially additive with gefitinib in the NHT group and additive/synergistic in the control group. Cultures (8/22) were negative for the expression of the PTEN gene and we observed no differences in the two groups. Thus the different IC50 values observed for gefitinib and the partial additivity in the combination treatment with gefitinib and BCLT is influenced by EGFR/Her2 ratio because it was shown that EGFR inhibition was lower when Her2 is overexpressed. Taken together, our results indicate that anti-EGFR targeted therapies and a possible combination therapy involving gefitinib and BCLT should be performed early in naive patients when Her2 is not overexpressed and before the anti-androgenic hormone therapy induces such an undesirable effect.
authors.affiliation: Department of Experimental Medicine, University of L'Aquila, 67100 L'Aquila, Italy. festucci@univaq.it.
authors.forename: Claudio
authors.initials: C
authors.lastname: Festuccia
authors.forename: Giovanni Luca
authors.initials: GL
authors.lastname: Gravina
authors.forename: Paola
authors.initials: P
authors.lastname: Muzi
authors.forename: Leda
authors.initials: L
authors.lastname: Biordi
authors.forename: Piero
authors.initials: P
authors.lastname: Ronchi
authors.forename: Oreste
authors.initials: O
authors.lastname: Martella
authors.forename: Carlo
authors.initials: C
authors.lastname: Vicentini
authors.forename: Mauro
authors.initials: M
authors.lastname: Bologna
mesh_terms: D000728:Androgens / Q000494:pharmacology*; D000813:Anilides / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D045744:Cell Line, Tumor / Q000187:drug effects; D004357:Drug Synergism; D000077156:Gefitinib; D006801:Humans; D008297:Male; D009570:Nitriles / Q000008:administration & dosage; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy*; D011799:Quinazolines / Q000008:administration & dosage; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D014105:Tosyl Compounds / Q000008:administration & dosage
chemical_list: D000728:Androgens; D000813:Anilides; D000077156:Gefitinib; D009570:Nitriles; D051059:PTEN Phosphohydrolase; D011799:Quinazolines; D018719:Erb-b2 Receptor Tyrosine Kinases; D014105:Tosyl Compounds; C053541:bicalutamide; C494929:PTEN protein, human