Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-like Pancreatic Cancer

Area of Science:

• Oncology
• Molecular Biology
• Metabolic Pathways

Background:

• Basal-like pancreatic ductal adenocarcinoma (PDAC) presents a significant clinical challenge due to its lethality and resistance to therapies.
• Keratin 17 (K17) upregulation correlates with poor prognosis in basal-like PDAC, indicating its potential role in tumor aggressiveness.

Purpose of the Study:

• To elucidate the molecular mechanisms driving basal-like PDAC.
• To identify therapeutic vulnerabilities in K17-expressing PDAC.

Main Methods:

• Investigated K17's role in de novo pyrimidine biosynthesis using cell lines and animal models.
• Utilized mitochondrial localization sequence (MLS) and TOM20 interaction studies.
• Assessed the impact of K17 inhibition and DHODH blockade on gemcitabine sensitivity.

Main Results:

• Identified intra-mitochondrial K17 as essential for de novo pyrimidine biosynthesis in basal-like PDAC.
• K17 stabilizes dihydroorotate dehydrogenase (DHODH) by preventing its degradation.
• Inhibition of K17 mitochondrial import or DHODH pharmacologic blockade sensitized PDAC cells to gemcitabine.
• Combined DHODH inhibition and gemcitabine treatment significantly reduced tumor growth and improved survival in K17⁺ PDAC mouse models.

Conclusions:

• K17 plays a critical mitochondrial role in sustaining pyrimidine biosynthesis in basal-like PDAC.
• Targeting K17-mediated metabolic pathways, specifically DHODH, represents a promising therapeutic strategy for K17⁺ PDAC, enhancing standard chemotherapy efficacy.