Poster Presentation 35th Lorne Cancer Conference 2023

Cooperativity between Hyaluronan Mediated Motility Receptor (HMMR) and Androgen receptor signalling regulates prostate cancer tumorigenesis. (#161)

Josephine Hinneh 1 2 3 4 , Joanna Gillis 1 4 , Chui Yan Mah 1 2 4 , Masashi Kato 3 , Maggie Centenera 1 2 4 , Lisa Butler 1 2 4
  1. South Australian Immunogenomics Cancer Institute and Adelaide Medical School, The University of Adelaide, Adelaide, South Australia, Australia
  2. Freemason’s Centre for Male Health and Wellbeing,, The University of Adelaide, Adelaide, South Australia, Australia
  3. Nagoya University Graduate School of Medicine, Nagoya University, Nagoya, Aichi, Japan
  4. Precision Cancer Medicine, The University of Adelaide, Adelaide, South Australia, Australia

Prostate cancer remains the most commonly diagnosed cancer and the second leading cause of cancer-related death in Australian men. The development and progression of PCa are dependent on androgen receptor (AR) signalling, and therefore the treatment for advanced PCa is androgen deprivation therapy (ADT). Despite an initial response to ADT, men inevitably progress to a lethal stage known as castration-resistant prostate cancer (CRPC) (3). CRPC remains reliant on AR signalling, rendering CRPC responsive to new generation AR targeting agents such as the antagonist, enzalutamide. However, enzalutamide provides only marginal survival benefits for patients, while the AR continues to drive treatment resistance.

We hypothesised that AR antagonists such as enzalutamide are not curative because they must not target the full complement of AR signalling in prostate cancer cells. If this is the case, AR-regulated genes untargeted by enzalutamide likely represent pro-survival factors that can be co-targeted for more durable suppression of prostate cancer cell growth.

RNA sequencing of LNCaP prostate cancer cells was undertaken to identify genes regulated by genetic (siRNA knockdown) versus pharmacological (enzalutamide) suppression of AR signalling. Genes that were uniquely regulated by AR knockdown but not by enzalutamide were prioritised for subsequent evaluation as potential therapeutic co-targets.

We identified hyaluronan mediated motility receptor (HMMR) as one of the most markedly regulated genes by AR knockdown but not by enzalutamide treatment. Furthermore, HMMR is a direct AR target gene overexpressed in prostate cancer compared to normal prostate tissues and its overexpression is associated with poorer patient outcomes. Knockdown or pharmacological inhibition of HMMR using siRNA or 4-methylubelliferone (4-MU) respectively, significantly and dose-dependently inhibited proliferation and induced apoptosis in multiple PCa cell lines. Additionally, culture with 4-MU dose-dependently inhibited cellular proliferation in patient-derived prostate tumour explants.

Importantly, in line with our original hypothesis, combination of 4-MU with enzalutamide synergistically suppressed PCa proliferation in vitro, in patient-derived explants and restricted tumour growth of mouse xenografts in vivo.

Taken together, this work has identified HMMR as a novel mechanism of resistance to AR targeting. Co-targeting of the AR and HMMR pathways warrants further investigation for the clinical management of advanced prostate cancer.