Keratin 17 Drives Chemoresistance in Pancreatic Cancer
Publication Title: Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer.
Summary
- Question
- This study investigated how keratin 17 (K17), a protein associated with aggressive pancreatic ductal adenocarcinoma (PDAC), contributes to resistance against gemcitabine, a standard chemotherapy drug. Specifically, the researchers explored whether K17’s presence in mitochondria plays a role in driving resistance through changes in cell metabolism.
- Why it Matters
- Pancreatic cancer, particularly the basal-like subtype of PDAC, is highly lethal and often resistant to chemotherapy. Understanding the mechanisms behind this resistance is crucial for developing targeted treatments. This study identifies K17 as a key player in promoting drug resistance, offering potential new strategies to improve outcomes for patients with this aggressive cancer.
- Methods
- The researchers used genetic models of human and mouse PDAC cells to manipulate K17 levels. They employed techniques such as metabolomics to analyze cellular metabolism, imaging to track K17’s location, and drug combination studies in cell cultures and mouse models to assess the impact of K17 on gemcitabine resistance. They also investigated the molecular interactions between K17 and mitochondrial proteins.
- Key Findings
- The study revealed that K17 localizes to the mitochondria through a specific sequence called a mitochondrial localization signal. In the mitochondria, K17 binds to and stabilizes dihydroorotate dehydrogenase (DHODH), an enzyme critical for producing pyrimidines—molecules necessary for DNA and RNA synthesis. This stabilization prevents DHODH degradation, increasing pyrimidine levels and enabling cancer cells to resist gemcitabine. In mouse models, combining gemcitabine with a DHODH inhibitor (brequinar) significantly reduced tumor growth and doubled survival in K17-positive tumors.
- Implications
- The findings suggest that K17 drives a metabolic pathway that fuels drug resistance in basal-like PDAC. By targeting DHODH or blocking K17’s mitochondrial entry, it may be possible to enhance the effectiveness of gemcitabine. Additionally, K17 could serve as a biomarker to identify patients who would benefit most from DHODH-targeted therapies, paving the way for more personalized treatment approaches.
- Next Steps
- The authors recommend further research to validate K17 as a biomarker for selecting patients likely to benefit from DHODH inhibitors. They also propose clinical trials to evaluate the combination of gemcitabine and DHODH inhibitors in patients with K17-positive pancreatic cancer.
- Funding Information
- This research was supported by the American Cancer Society (grant PF-25-1422234-01-PFCBI), the National Institutes of Health (grants K99-R00CA226342, R01CA274355, and DP2CA280625). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Full Citation
Pan C, Lyu Y, Ghosh M, Siraj M, Tseng R, Chaika N, Haley J, Khalvatifahlylani B, Tuveson D, Patel H, Faruque M, Rajacharya G, Donnelly K, Leiton C, Mejia Arbelaez C, Chen H, Chowdhury S, Sarkar S, Delgado Coka L, Roa-Peña L, Horowitz M, Marchenko N, Singh P, Shroyer K, Escobar-Hoyos L. Mitochondrial-Localized Keratin 17 Promotes Chemoresistance in Basal-Like Pancreatic Cancer. Cancer Research 2026 PMID: 41817415, DOI: 10.1158/0008-5472.can-25-4534.
This AI-assisted summary has been reviewed and approved by at least one of the study's authors to ensure it accurately reflects the research.
Authors
Chun-Hao Pan
First AuthorLuisa Escobar-Hoyos, MSc, PhD
Last AuthorAssistant Professor of Therapeutic Radiology
Other Authors
Research Themes
Concepts
- Mitochondrial localization sequence;
- Pyrimidine biosynthesis;
- Dihydroorotate dehydrogenase;
- Enzymes of de novo pyrimidine biosynthesis;
- De novo pyrimidine biosynthesis;
- Mitochondrial intermembrane space;
- Pancreatic ductal adenocarcinoma;
- Basal-like molecular subtype;
- Pharmacological inhibition;
- Ubiquitination-mediated degradation;
- Inhibition of dihydroorotate dehydrogenase;
- Intermembrane space;
- Mitochondrial role;
- Localization sequence;
- Cells to gemcitabine;
- Keratin 17;
- Metabolic vulnerabilities;
- Biosynthesis;
- Molecular mechanisms;
- Molecular subtypes of pancreatic ductal adenocarcinoma;
- Subtype of pancreatic ductal adenocarcinoma;
- Mitochondria;
- Standard chemotherapeutic agents;
- Associated with poor patient outcomes;
- Aggressive tumor subtype