Mitochondrial fusion exploits a therapeutic vulnerability of pancreatic cancer

Area of Science:

• Mitochondrial biology
• Cancer research
• Drug repurposing

Background:

• Pancreatic ductal adenocarcinoma (PDAC) relies on mitochondrial oxidative phosphorylation (OXPHOS) for growth.
• PDAC cells have fragmented mitochondria, but their therapeutic potential was unclear.
• Targeting OXPHOS broadly risks disrupting normal tissue function.

Purpose of the Study:

• To investigate if normalizing mitochondrial fragmentation via fusion is a viable therapeutic strategy for PDAC.
• To identify mechanisms by which mitochondrial fusion impacts cancer progression.
• To explore the potential of repurposing existing drugs for PDAC treatment.

Main Methods:

• Inducing mitochondrial fusion genetically (inhibiting dynamin related protein-1 [Drp1] or overexpressing mitofusin-2 [Mfn2]).
• Pharmacologically inhibiting Drp1.
• Administering leflunomide, an FDA-approved drug, to assess its effect on Mfn2 expression and tumor growth.
• Measuring oxidative phosphorylation (OXPHOS), mitophagy, mitochondrial mass, and ATP production in preclinical models.

Main Results:

• Mitochondrial fusion normalized fragmented mitochondria in PDAC cells.
• This normalization reduced OXPHOS, suppressed tumor growth, and improved survival in preclinical models.
• Leflunomide increased Mfn2 expression twofold, improved median survival by 50%, and enhanced mitophagy, reducing mitochondrial mass and ATP production.

Conclusions:

• Mitochondrial fusion is a specific and druggable target for pancreatic cancer.
• Enhanced mitophagy is the primary mechanism by which mitochondrial fusion exerts its tumor-suppressive effects.
• Repurposed leflunomide shows promise as a novel chemotherapeutic agent for PDAC, warranting rapid clinical translation.