Sprouty2 loss-induced IL6 drives castration-resistant prostate cancer through scavenger receptor B1

Area of Science:

• Oncology
• Molecular Biology
• Biochemistry

Background:

• Metastatic castration-resistant prostate cancer (mCRPC) presents significant treatment challenges.
• Loss of the tumor suppressor Sprouty2 (SPRY2) is linked to resistance in mCRPC by deregulating receptor tyrosine kinase (RTK) signaling.
• SPRY2 deficiency can lead to an androgen-independent form of cancer.

Purpose of the Study:

• To investigate the mechanism by which SPRY2 deficiency promotes castration-resistant prostate cancer (CRPC).
• To explore the role of cholesterol metabolism and transport in SPRY2-deficient CRPC.
• To evaluate the therapeutic potential of targeting cholesterol transport in this context.

Main Methods:

• Utilized pre-clinical human and murine mCRPC models with SPRY2 deficiency.
• Investigated the HER2-IL6 signaling axis and its impact on androgen biosynthesis and cholesterol uptake.
• Assessed the effect of SRB1 antagonist ITX5061 on treatment resistance in SPRY2-deficient models.

Main Results:

• SPRY2 deficiency results in an androgen self-sufficient CRPC phenotype.
• The HER2-IL6 pathway upregulates HSD3B1 (androgen synthesis enzyme) and SRB1-mediated cholesterol uptake in SPRY2-deficient tumors.
• IL6 increases systemic cholesterol via lipolysis and hepatic synthesis, making SPRY2-deficient CRPC dependent on cholesterol bioavailability.
• Treatment with the SRB1 antagonist ITX5061 reduced treatment resistance.

Conclusions:

• SPRY2-deficient CRPC relies on cholesterol for androgen biosynthesis, facilitated by SRB1-mediated uptake.
• Targeting cholesterol transport, specifically via SRB1 antagonism, shows promise for treating SPRY2-deficient mCRPC.
• Blocking cholesterol transport represents a potential therapeutic strategy against treatment-resistant prostate cancer.