Prostate Cancer Cells With the AR-Low and EMT-High Phenotype Are Vulnerable to NAD+ Synthesis Inhibitors

Area of Science:

• Oncology
• Molecular Biology
• Cancer Therapeutics

Background:

• Metastatic prostate cancer treatment relies on targeting androgen receptor (AR) signaling, but resistance is common, leading to poor outcomes.
• Understanding the mechanisms and vulnerabilities of treatment-resistant prostate cancer is crucial for improving patient survival.
• A novel AR-low/EMT-high resistant cell model was established to investigate resistance mechanisms.

Purpose of the Study:

• To characterize the molecular mechanisms and identify vulnerabilities in a newly established AR-low/EMT-high prostate cancer treatment-resistant cell model.
• To determine if identified metabolic vulnerabilities can be therapeutically exploited to overcome enzalutamide resistance.
• To assess the clinical relevance of the identified phenotype and vulnerability in patient samples.

Main Methods:

• Transcriptome analysis (bulk RNA-Seq, qRT-PCR) and ChIP-qPCR were used to profile resistant cells.
• Metabolic assays, siRNA, and overexpression studies identified a metabolic vulnerability.
• Proliferation, colony formation, and live-cell imaging assays assessed the efficacy of small molecule inhibitors combined with enzalutamide.
• Prostate cancer TCGA data was analyzed for clinical relevance.

Main Results:

• The AR-low resistant cells displayed an EMT-high phenotype, distinct from sensitive cells.
• A deficiency in NAPRT (nicotinamide adenine dinucleotide+ biosynthesis enzyme) was identified as a metabolic vulnerability in resistant cells.
• Targeting NAPRT deficiency with NAD+ biosynthesis inhibitors enhanced enzalutamide efficacy in vitro and was associated with AR-low/EMT-high phenotypes in patient samples.

Conclusions:

• The established AR-low/EMT-high resistant cell model reflects a clinically relevant phenotype associated with enzalutamide resistance.
• NAPRT deficiency represents a novel vulnerability in AR-low/EMT-high prostate cancer.
• Targeting NAPRT with NAD+ inhibitors offers a potential strategy to improve enzalutamide efficacy in resistant prostate cancer.