Multiomics combined with machine learning defines unique molecular subtypes of cholangiocarcinoma and identifies TNK1 as a therapeutic target.

Journal: Hepatology (Baltimore, Md.)
Published Date: Sep 29, 2025

Abstract

BACKGROUND AND AIMS: Cholangiocarcinoma (CCA) is one of the most lethal cancers, characterized by molecular heterogeneity and treatment resistance. To uncover new biological signals and therapeutic opportunities, we employed multiomic characterization combined with machine learning. APPROACH AND RESULTS: We profiled all anatomical CCA subtypes using whole exome sequencing, mRNA sequencing, and proteome/phosphoproteome analysis. Integrative dimensional reduction revealed RNA, protein, and phosphoprotein features driving tumor heterogeneity, enabling clustering. Machine learning algorithms identified molecular features for each cluster and mapped external datasets and patient-derived xenograft (PDX) models onto these clusters. Kinase enrichment analysis highlighted targetable kinases active in each cluster. In vivo validation was performed in cluster-specific PDX models using the selective TNK1 inhibitor, TP-5801. We identified 3 molecular clusters with distinct pathway characterization: immunomodulatory (cluster 1), metabolic (cluster 2), and gene regulation/cellular fate (cluster 3). Cluster assignment was independent of anatomic subtype but correlated with overall survival following curative-intent resection. We also identified multiomic features and pathways linked to overall survival and lymph node metastases, crucial for patient treatment selection. Kinase enrichment analysis pinpointed TNK1 as a highly active kinase in the metabolic cluster. Treatment with TP-5801 significantly reduced tumor growth in a metabolic PDX model, but not in models representing the other clusters. Combining internal data with publicly available datasets, we identified the immunomodulatory cluster as most responsive to gemcitabine/cisplatin therapy, confirmed in vivo using cluster-specific PDX models. CONCLUSIONS: Integrated multiomic characterization provides translational insights by defining unique molecular subtypes associated both with therapeutic response and overall clinical outcomes. This approach identified TNK1 as a previously unrecognized therapeutic target in a defined subset of CCA tumors.

Authors

  • Dong-Gi Mun
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Erik Jessen
    Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Jennifer L Tomlinson
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Danielle Carlson
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Rohit Budhraja
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Roberto Alva-Ruiz
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Amro Abdelrahman
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Ryan Watkins
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Lindsey Gregory
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Chantal McCabe
    Department of Quantitative Health Sciences, Mayo Clinic, Rochester, MN, USA.
  • Chen Wang
    Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • Rondell P Graham
    Mayo Clinic, Rochester, MN, USA.
  • Kathryn Woods
    Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • Martin Golkowski
    Department of Pharmacology and Toxicology, University of Utah, Salt Lake City, UT, USA.
  • Marshall Baker
    Department of Surgery, Loyola University Medical Center, Maywood, IL; Edward Hines, Jr Veterans Administration Hospital, Hines, IL.
  • Gregory J Gores
    Division of Gastroenterology &, Hepatology Mayo Clinic, Rochester, MN.
  • Sumera I Ilyas
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
  • Caitlin Conboy
    Division of Hematology and Oncology, Mayo Clinic, Rochester, MN, USA.
  • Ellen L Larson
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Jack W Sample
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Enis H Ozmert
    Department of Surgery, Mayo Clinic, Rochester, MN, USA.
  • Richard K Kandasamy
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
  • Mitesh J Borad
    Division of Hematology and Oncology, Mayo Clinic, Scottsdale, AZ, USA.
  • Lewis Roberts
    Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
  • Joshua Andersen
    Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, USA.
  • Akhilesh Pandey
    Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, United States.
  • Rory L Smoot
    Department of Surgery, Division of Hepatobiliary and Pancreas Surgery, Mayo Clinic, Rochester, MN, USA.

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