The AR is a transcription factor that plays a major physiological role in normal male sexual development and contributes to the progression of prostate cancer. About one-third of prostate cancer patients develop metastatic disease and receive treatment to block androgen production and the AR itself. Unfortunately, although this treatment may work for some time, the disease eventually enters an androgen-refractory period where the signaling molecules downstream of the AR are active even with very low levels of androgen.
A considerable amount of effort has gone into dissecting the signaling pathways that regulate the AR to look for pharmacological tools that can attenuate abnormal AR function. Dr. Charles L. Sawyers and colleagues from the David Geffen School of Medicine at UCLA used a small molecule dual kinase inhibitor to closely examine two molecules that interact with one another and are known to enhance AR function, ERBB family members EGFR and HER2. Previous work has strongly implicated EGFR as being a key modulator of AR. Interestingly, the Sawyers group found that HER2, but not EGFR signals, were required for optimal AR function. HER2 was shown to promote AR stability and function, not via interactions with EGFR, but by associating with other ERBB family members.
The researchers conclude that AR function is modulated by the HER2/ERBB3 pathway and not by EGFR, as was previously believed. These results are particularly relevant because they may explain the limited success of Gefitinib, an EGFR inhibitor recently
Contact: Heidi Hardman