NEW YORK (Reuters Health) - California-based cancer researchers have evidence that androgen receptor (AR) function is modulated by the HER2/ERBB3 pathway -- not by the epidermal growth factor receptor (EGFR)/HER2 pathway, as previous work has suggested.
“Our findings provide novel insights into AR function and suggest that successful application of ERBB kinase family inhibitors in hormone-refractory prostate cancer may require specific targeting of the HER2/ERBB3 heterodimer complex,” Dr. Ingo K. Mellinghoff and colleagues from the David Geffen School of Medicine at UCLA point out in the November issue of the journal Cancer Cell.
Moreover, they say their findings may help explain the disappointing activity of the EGFR inhibitor gefitinib (Iressa) in recent prostate cancer trials.
The androgen receptor has emerged as a key player in the progression of prostate cancer to a hormone-refractory state. The UCLA team conducted a series of experiments in human cell cultures and in mice aimed at dissecting the interplay between ERBB receptor tyrosine kinases and AR function.
They discovered, somewhat surprisingly, that HER2 signals, not EGFR signals, are required for optimal AR function at low androgen levels and that “modulation of AR function is mediated by the HER2/ERBB3 pathway, not by EGFR.”
HER2/ERBB3 signaling promotes AR protein stability and function, according to the investigators.
“We have defined a HER2-dependent signal that is critical for AR function at low androgen concentrations,” the team writes. “Our finding that this signal is EGFR-independent shifts the emphasis from the EGFR/HER2-MAPK axis to the HER2/ERBB3 axis,” they add.
Support for this switch can be found in other preclinical studies in which interruption of the HER2/ERBB3 pathway with a monoclonal antibody (2C4) impressively inhibited the growth of hormone-refractory prostate cancer xenografts, whereas trastuzumab, which does not block HER2/ERBB3, had minimal activity. (see Reuters Health report August 13, 2002)
Source: Cancer Cell 2004;6:517-527. [ Google search on this article ]
MeSH Headings:Receptors, Androgen: Receptors, Steroid: Transcription Factors: Receptors, Cytoplasmic and Nuclear: Genes, erbB-2: Genes, erbBCopyright © 2002 Reuters Limited. All rights reserved. Republication or redistribution of Reuters content, including by framing or similar means, is expressly prohibited without the prior written consent of Reuters. Reuters shall not be liable for any errors or delays in the content, or for any actions taken in reliance thereon. Reuters and the Reuters sphere logo are registered trademarks and trademarks of the Reuters group of companies around the world.
