Blocking lipid synthesis induces DNA damage in prostate cancer and increases cell death caused by PARP inhibition

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Androgen deprivation therapy (ADT) is standard for prostate cancer, but resistance leads to castration-resistant prostate cancer (CRPC).
• Fatty acid synthase (FASN) is overexpressed in CRPC, driving fatty acid synthesis and cancer progression, making it a therapeutic target.
• FASN inhibition increases ceramides and sphingomyelin, inducing DNA damage and cell death.

Purpose of the Study:

• To investigate the efficacy of combining a FASN inhibitor (FASNi) with a poly-ADP ribose polymerase (PARP) inhibitor (olaparib) for CRPC treatment.
• To determine if this combination therapy enhances cell death and reduces tumor growth compared to monotherapy.

Main Methods:

• Treatment of human CRPC organoids with a FASNi and olaparib.
• Assessment of cell proliferation, apoptosis, necrosis, and overall organoid size.

Main Results:

• The combination therapy significantly reduced cell growth more than either drug alone.
• CRPC organoids treated with the combination showed decreased proliferation, increased apoptosis, and necrosis.
• Tumor organoids treated with the combination were smaller compared to controls.

Conclusions:

• Targeting FASN enhances the therapeutic efficacy of PARP inhibitors in CRPC by impairing DNA damage repair.
• Combination therapy with FASNi and PARP inhibitors represents a promising strategy for CRPC treatment and warrants further clinical investigation.