Additive antitumor effects of the epidermal growth factor receptor tyrosine kinase inhibitor, gefitinib (Iressa), and the nonsteroidal antiandrogen, bicalutamide (Casodex), in prostate cancer cells in vitro.
Progression from an androgen-dependent to an androgen-independent state often occurs in patients with prostate cancer (PCa) who undergo hormonal therapy. We have investigated whether inhibition of the epidermal growth factor receptor (EGFR) signaling pathway affects the antitumor effect of a nonsteroidal antiandrogen. Gefitinib (Iressa), an EGFR tyrosine kinase inhibitor, and bicalutamide (Casodex), a nonsteroidal antiandrogen [androgen receptor (AR) antagonist], were administered alone and in combination to AR-positive human PCa cell lines. FACS analysis showed lower EGFR expression levels on AR-positive cells (LNCaP, CWR22, CWR22R 2152 and AR-transfected DU145 cell lines) compared with AR-negative cells (DU145, PC3 and TSU-Pr1). Moreover, in AR-transfected DU145 cells, chronic treatment with bicalutamide increased EGFR expression to levels similar to androgen-independent DU145 cells. All AR-positive PCa cell lines were sensitive to gefitinib (IC50 = 0.1-0.6 microM), whereas higher concentrations of bicalutamide were needed to reduce AR-positive PCa cell line proliferation (IC50 = 0.8-2.0 microM). Low doses of gefitinib increased the antitumor effects of bicalutamide by strongly reducing the IC50 of bicalutamide (approximately 10-fold). Similarly, bicalutamide increased the antiproliferative effects of gefitinib by reducing the IC50 of gefitinib (approximately 5-fold). Taken together, our data suggest that in androgen-dependent cell lines, addition of gefitinib in combination with bicalutamide results in concurrent dual inhibition of AR and EGFR/HER2 pathways. This causes a significant delay in the onset of EGFR-driven androgen independence.
Festuccia
Claudio
C
Department of Experimental Medicine, University of L'Aquila, L'Aquila, Italy. festucci@univaq.it
Gravina
Giovanni Luca
GL
Angelucci
Adriano
A
Millimaggi
Danilo
D
Muzi
Paola
P
Vicentini
Carlo
C
Bologna
Mauro
M
D000726:Androgen Antagonists / Q000633:toxicity; D000813:Anilides / Q000633:toxicity*; D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity; D002455:Cell Division / Q000187:drug effects; D045744:Cell Line, Tumor; D013196:Dihydrotestosterone / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000077156:Gefitinib; D006801:Humans; D008297:Male; D009570:Nitriles; D011471:Prostatic Neoplasms / Q000473:pathology*; D011799:Quinazolines / Q000633:toxicity*; D014105:Tosyl Compounds; D014183:Transplantation, Heterologous
D000726:Androgen Antagonists; D000813:Anilides; D000970:Antineoplastic Agents; D009570:Nitriles; D011799:Quinazolines; D014105:Tosyl Compounds; D013196:Dihydrotestosterone; D004815:Epidermal Growth Factor; C053541:bicalutamide; D066246:ErbB Receptors; D000077156:Gefitinib