Abstract
Metastatic castration‐resistant prostate cancer (mCRPC) is a lethal form of treatment‐resistant prostate cancer and poses significant therapeutic challenges. Deregulated receptor tyrosine kinase (RTK) signalling mediated by loss of tumour suppressor Sprouty2 (SPRY2) is associated with treatment resistance. Using pre‐clinical human and murine mCRPC models, we show that SPRY2 deficiency leads to an androgen self‐sufficient form of CRPC. Mechanistically, HER2‐IL6 signalling axis enhances the expression of androgen biosynthetic enzyme HSD3B1 and increases SRB1‐mediated cholesterol uptake in SPRY2‐deficient tumours. Systemically, IL6 elevated the levels of circulating cholesterol by inducing host adipose lipolysis and hepatic cholesterol biosynthesis. SPRY2‐deficient CRPC is dependent on cholesterol bioavailability and SRB1‐mediated tumoral cholesterol uptake for androgen biosynthesis. Importantly, treatment with ITX5061, a clinically safe SRB1 antagonist, decreased treatment resistance. Our results indicate that cholesterol transport blockade may be effective against SPRY2‐deficient CRPC.
Highlights
Prostate cancer is the most common malignancy in men
Consistent with our previous reports on co-occurrence of SPRY2 and PTEN alterations in prostate cancer (Gao et al, 2012; Patel et al, 2013), SPRY2 and PTEN levels significantly correlated in castration-resistant prostate cancer (CRPC) (Fig EV1C)
Since SPRY2 expression was progressively lost from HN state to CRPC, we hypothesised that SPRY2 deficiency may modulate tumour response to Androgen deprivation therapy (ADT)
Summary
Prostate cancer is the most common malignancy in men. Treatment resistance and cancer dissemination are the major causes of diseaseassociated mortalities in most advanced cancers, including prostate cancer. Androgens and androgen receptor (AR) are essential for growth and survival of prostate cancer (Yap et al, 2016). Androgen deprivation therapy (ADT) administered through surgical or medical castration remains the current initial treatment for metastatic prostate cancer. Despite an initial favourable response to ADT (even when combined with upfront docetaxel chemotherapy), a majority of the patients will progress to an advanced disease state termed castration-resistant prostate cancer (CRPC). A subset of the emerging CRPC may exhibit AR-independent characteristics, AR reactivation remains as a significant feature of advanced disease (Watson et al, 2015)
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