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Epidermal Growth Factor Receptor Monoclonal Antibody Inhibits Constitutive Receptor Phosphorylation, Reduces Autonomous Growth, and Sensitizes Androgen-independent Prostatic Carcinoma Cells to Tumor Necrosis Factor ¹

Urological Oncology Program, Department of Urology, Northwestern University Medical School, Chicago, Illinois 60611 [C-J. F., E. R. S., C. L., J. M. K.], and Laboratory of Receptor Biology, Memorial Sloan-Kettering Cancer Center, New York, New York 10021 [J. M.]

Results of recent studies indicate that cultured, androgen-independent prostatic carcinoma cells synthesize and secrete transforming growth factor , which interacts with epidermal growth factor receptors (EGFRs) to promote autonomous growth. In the present study, we evaluated the expression and constitutive activation of EGFRs in normal prostatic epithelial cells and the androgen-independent prostatic carcinoma cell lines PC3 and DU145. Our studies showed that cultured normal epithelial cells and androgen-independent prostatic carcinoma cells actively synthesize and exhibit constitutive phosphorylation of the M_r 170,000 EGFR. The addition of monoclonal anti-EGFR reduced receptor phosphorylation and significantly inhibited the proliferation of prostatic tumor cells. The observed reduction in EGFR phosphorylation could be partially attributed to an antibody-induced decrease in the expression of metabolically labeled EGFR. Results of further studies showed that anti-EGFR enhanced the sensitivity of PC3 cells to the cytotoxic and cytostatic effects of tumor necrosis factor . These studies demonstrate that constitutive activation of EGFR in androgen-independent prostatic carcinoma plays a functional role in the regulation of cellular proliferation in vitro. In addition, the enhanced sensitivity of prostatic carcinoma cells to tumor necrosis factor in the presence of anti-EGFR provides a rationale for the further investigation of combination therapy in the treatment of disseminated, androgen-independent disease.

¹ Supported by NIH Grant DK39250 and the Lucy and Edwin Kretschmer Fund of Northwestern University Medical School.

² Recipient of the William O. Jeffery III Fellowship for Prostate Cancer Research of Northwestern University Medical School and a Medical Student Research Fellowship from the American Foundation for Urological Disease. To whom requests for reprints should be addressed, at Northwestern University, Department of Urology, Tarry Building 11-715, 303 East Chicago Avenue, Chicago, IL 60611-3009.

Received 12/10/91. Accepted 8/25/92.

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