itx-5061 and Prostatic-Neoplasms--Castration-Resistant

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.

Topics: Animals; Humans; Interleukin-6; Intracellular Signaling Peptides and Proteins; Male; Membrane Proteins; Mice, Nude; Phenylenediamines; Prostatic Neoplasms, Castration-Resistant; Protein Serine-Threonine Kinases; Real-Time Polymerase Chain Reaction; Receptor, ErbB-2; Receptors, Scavenger; Scavenger Receptors, Class B; Signal Transduction; Sulfonamides