Growth inhibitory effects of the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human prostate cancer xenografts.

Abstract

Experiments with human prostate cancer cell lines have shown that forced overexpression of the ErbB2-receptor tyrosine kinase (RTK) promotes androgen-independent growth and increases androgen receptor-transcriptional activity in a ligand-independent fashion. To investigate the relationship between ErbB-RTK signaling and androgen in genetically unmanipulated human prostate cancer, we performed biochemical and biological studies with the dual ErbB1/ErbB2 RTK inhibitor PKI-166 using human prostate cancer xenograft models with isogenic sublines reflecting the transition from androgen-dependent to androgen-independent growth. In the presence of low androgen concentrations, PKI-166 showed profound growth-inhibitory effects on tumor growth, which could be partially reversed by androgen add-back. At physiological androgen concentrations, androgen withdrawal greatly enhanced the ability of PKI-166 to retard tumor growth. The level of extracellular signal-regulated kinase activation correlated with the response to PKI-166 treatment, whereas the expression levels of ErbB1 and ErbB2 did not. These results suggest that ErbB1/ErbB2 RTKs play an important role in the biology of androgen-independent prostate cancer and provide a rationale for clinical evaluation of inhibitors targeted to this pathway.

• Authors: Ingo K Mellinghoff, Chris Tran, Charles L Sawyers
• Journal: Cancer research (Cancer Res) Vol. 62 Issue 18 Pg. 5254-9 (Sep 15 2002) ISSN: 0008-5472 [Print] United States
• PMID: 12234993 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S., Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Androgens
• Growth Inhibitors
• Pyrimidines
• Pyrroles
• PKI 166
• ErbB Receptors
• Receptor, ErbB-2

Topics

• Androgens (blood, physiology)
• Animals
• Cell Division (drug effects)
• ErbB Receptors (antagonists & inhibitors)
• Growth Inhibitors (pharmacology)
• Humans
• Male
• Mice
• Mice, SCID
• Prostatic Neoplasms (drug therapy, enzymology, pathology)
• Pyrimidines (pharmacology)
• Pyrroles (pharmacology)
• Receptor, ErbB-2 (antagonists & inhibitors)
• Signal Transduction (drug effects)
• Tumor Cells, Cultured
• Xenograft Model Antitumor Assays