Targeting NDUFS4 Disrupts Oxidative Phosphorylation and Induces Ferroptosis in Olaparib-Resistant Prostate Cancer

Area of Science:

• Oncology
• Metabolic pathways
• Mitochondrial biology

Background:

• PARP inhibitors (PARPi) are crucial for treating advanced prostate cancer.
• Resistance to PARPi is a significant clinical challenge, often linked to metabolic alterations.
• The specific molecular mechanisms driving PARPi resistance and potential vulnerabilities are not well understood.

Purpose of the Study:

• To identify mitochondrial regulators involved in PARPi resistance in prostate cancer.
• To explore NDUFS4 as a potential therapeutic target for overcoming PARPi resistance.

Main Methods:

• Integrated transcriptomic, functional, and clinical data analyses.
• RNA sequencing and gene set enrichment analysis to identify key pathways and genes.
• Genetic knockdown and pharmacologic inhibition of NDUFS4 in prostate cancer models.
• Assessment of mitochondrial function, cell viability, and ferroptosis markers.

Main Results:

• PARPi-resistant prostate cancer cells exhibit upregulated oxidative phosphorylation pathways, notably NDUFS4.
• Elevated NDUFS4 expression correlates with poorer patient survival.
• NDUFS4 knockdown or inhibition with ARVib-7 impairs mitochondrial respiration, reduces mitochondrial mass, and re-sensitizes cells to olaparib.
• Targeting NDUFS4 induces ferroptosis, characterized by iron accumulation and altered ferroptosis markers.

Conclusions:

• NDUFS4 is a key mediator of PARPi resistance in advanced prostate cancer.
• Targeting NDUFS4 disrupts mitochondrial function and induces ferroptosis, presenting a therapeutic vulnerability.
• Combination strategies involving PARP inhibitors and NDUFS4-targeting agents show promise for overcoming treatment resistance.