Inhibition of IGF-1R diminishes transcriptional activity of the androgen receptor and its constitutively active, C-terminally truncated counterparts Q640X and AR-V7.

PURPOSE: Failure of endocrine treatment in castration-resistant prostate cancer (CRPC) is often associated with the emergence of C-terminally truncated androgen receptor variants that function as constitutively active transcription factors (i.e., AR∆LBD). The mechanisms involved in the regulation of AR∆LBD signaling are largely unknown. Since the IGF-1 pathway was repeatedly shown to affect AR function, we studied whether an inhibition of IGF-1R could also affect AR∆LBD signaling.
METHODS: Regulation of androgen receptor (AR) and AR∆LBD signaling was analyzed by reporter gene assays, immunoblotting, ELISA and quantitative RT-PCR.
RESULTS: Inhibition of IGF-1R with the small-molecule inhibitor NVP-AEW541 reduced the transcriptional activity of the AR and its truncated counterparts Q640X and AR-V7. As shown in Q640X, the inhibition of transcriptional activity was paralleled by a decreased receptor phosphorylation.
CONCLUSIONS: Inhibition of IGF-1R leads to a down-regulation of AR∆LBD signaling and provides a rationale for CRPC therapies targeting growth factor receptors.