Over the past decade, treatment options for patients with metastatic prostate cancer have dramatically increased, improving disease control by prolonging progression-free survival and overall survival. However, every patient with metastatic prostate cancer who receives a first line of systemic treatment will eventually develop therapy resistance.

This resistance, particularly to docetaxel and hormones, makes finding new therapeutic strategies crucial.
Docetaxel is one of the most established chemotherapy regimens for prostate cancer and remains a cornerstone in the treatment of patients. Combining docetaxel with second-generation hormonal therapy has shown improved progression-free and overall survival. However, therapy resistance significantly limits the efficacy of chemotherapy.
A new study published in The American Journal of Pathology found that inhibition of the sterol regulatory element-binding protein (SREBP) can reinduce sensitivity to docetaxel in prostate cancer. This discovery holds promise for improving the efficacy of docetaxel-based chemotherapy.
The study investigated the effects of combining docetaxel and mifepristone in docetaxel-resistant prostate cancer cell models. This combination significantly reduced cancer cell viability. RNA sequencing identified sterol regulatory element-binding transcription factor 1 (SREBF-1) as a significantly down-regulated target. SREBF-1 is a transcription factor involved in cholesterol and lipid biosynthesis.
The researchers determined that SREBF-1 is a central cellular regulator involved in docetaxel-resistant prostate cancer. Specifically inhibiting cholesterol and lipid biosynthesis reinduced sensitivity to docetaxel. Further analysis of a tissue microarray from tumor tissue of advanced prostate cancer patients revealed that SREBPs are increasingly expressed in metastatic prostate cancer.
These findings suggest that SREBPs are essential regulators of cell survival and susceptibility to docetaxel in advanced and metastatic prostate cancer, affecting prostate cancer aggressiveness and docetaxel resistance. Inhibiting cholesterol and lipid biosynthesis might provide a clinically meaningful approach to increasing the efficacy of prostate cancer therapies, particularly in drug-resistant cases.

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