Resistance to androgen receptor signalling inhibitors (ARSIs) represents a major clinical challenge in prostate cancer. We previously demonstrated that the ARSI enzalutamide inhibits only a subset of all AR-regulated genes, and hypothesise that the unaffected gene networks represent potential targets for therapeutic intervention. This study identified the hyaluronan-mediated motility receptor (HMMR) as a survival factor in prostate cancer and investigated its potential as a co-target for overcoming resistance to ARSIs.
RNA-seq, RT-qPCR and Western Blot were used to evaluate the regulation of HMMR by AR and ARSIs. HMMR inhibition was achieved via siRNA knockdown or pharmacological inhibition using 4-methylumbelliferone (4-MU) in prostate cancer cell lines, a mouse xenograft model and patient-derived explants (PDEs).
HMMR was an AR-regulated factor that was unaffected by ARSIs. Genetic (siRNA) or pharmacological (4-MU) inhibition of HMMR significantly suppressed growth and induced apoptosis in hormone-sensitive and enzalutamide-resistant models of prostate cancer. Mechanistically, 4-MU inhibited AR nuclear translocation, AR protein expression and subsequent downstream AR signalling. 4-MU enhanced the growth-suppressive effects of 3 different ARSIs in vitro and, in combination with enzalutamide, restricted proliferation of prostate cancer cells in vivo and in PDEs.
Co-targeting HMMR and AR represents an effective strategy for improving response to ARSIs.
British journal of cancer. 2023 Sep 06 [Epub ahead of print]
Josephine A Hinneh, Joanna L Gillis, Chui Yan Mah, Swati Irani, Raj K Shrestha, Natalie K Ryan, Enomoto Atsushi, Zeyad D Nassar, David J Lynn, Luke A Selth, Masashi Kato, Margaret M Centenera, Lisa M Butler
South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, 5000, Australia., Freemason's Centre for Male Health and Wellbeing, University of Adelaide, Adelaide, SA, 5000, Australia., Department of Pathology, Nagoya University Graduate School of Medicine, Nagoya, Japan., Precision Cancer Medicine Theme, South Australian Health and Medical Research Institute, Adelaide, SA, 5000, Australia., Department of Urology, Nagoya University Graduate School of Medicine, Nagoya, Japan., South Australian Immunogenomics Cancer Institute, University of Adelaide, Adelaide, SA, 5000, Australia. .