2. Academic Validation
  3. KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer

KRAS Signaling Inhibition Induces a Targetable Metabolic Dependency on Lipophagy-Dependent Fatty Acid Oxidation in Pancreatic Cancer

  • Cancer Res. 2026 Apr 29:10.1158/0008-5472.CAN-24-1984. doi: 10.1158/0008-5472.CAN-24-1984.
Ravi Thakur 1,  Dezhen Wang 2,  Tuo Hu 3,  Chunbo He 4,  Junzhang Zhao 5,  Voddu Suresh 5,  Girish H Rajacharya 6,  Anjan K Pradhan 5,  Vira Chumak 5,  Carlos A Valenzuela 5,  Asha D Kushwaha 5,  Drew A Labreck 5,  Tae Gyu Oh 7,  Kar-Ming Fung 4,  Daniel Zhao 8,  Naoko Takebe 4,  Susanna V Ulahannan 9,  Surendra K Shukla 9,  Kirsten L Bryant 10,  Channing J Der 11,  Kamiya Mehla 8,  Pankaj K Singh 12
Affiliations

Affiliations

  • 1 Christ University Bengaluru, Karnataka India.
  • 2 University of Pennsylvania Philadelphia, PA United States.
  • 3 University of Nebraska Medical Center Omaha, NE United States.
  • 4 University of Oklahoma Health Sciences Center Oklahoma City, Oklahoma United States.
  • 5 University of Oklahoma Health Sciences Center OKLAHOMA CITY, OKLAHOMA United States.
  • 6 University of Oklahoma Health Sciences Center Oklahoma city, Oklahoma United States.
  • 7 University of Oklahoma Health Science Center Oklahoma City, Oklahoma United States.
  • 8 University of Oklahoma Health Sciences Center Oklahoma City United States.
  • 9 University of Oklahoma Health Sciences Center United States.
  • 10 University of North Carolina at Chapel Hill Chapel Hill United States.
  • 11 University of North Carolina at Chapel Hill Chapel Hill, NC United States.
  • 12 University of Oklahoma Health Sciences Center Oklahoma City, OK United States.
PMID: 42054558 DOI: 10.1158/0008-5472.CAN-24-1984
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is characterized by frequent KRAS mutations, which activate the MAPK pathway to promote PDAC progression. Here, we explored metabolic vulnerabilities of PDAC by assessing initial metabolic reprogramming upon ERK inhibition using metabolomics, lipidomics, and isotope-tracing experiments. ERK inhibition enhanced lipid turnover and fatty acid oxidation while inhibiting glycolysis, glucose oxidation, and glutamine metabolism in PDAC cells. Moreover, lipophagy, but not cytosolic lipolysis, was responsible for the increased lipid turnover and fatty acid oxidation upon ERK inhibition. Lipophagy and lipophagy-fueled fatty acid oxidation were induced by increased nuclear translocation and activity of the transcription factor TFEB. Pharmacological inhibition of fatty acid oxidation in combination with KRASG12D/MEK/ERK inhibitors synergistically decreased the growth of PDAC cell lines and organoids. The combination decreased tumor burden and improved survival in orthotopic cell line and patient-derived xenograft PDAC models. Overall, this study provides mechanistic insights into the development of metabolic resistance to KRAS signaling inhibition and demonstrates that fatty acid oxidation is a metabolic vulnerability following KRAS signaling inhibition that can be utilized as an effective therapeutic target to treat PDAC.

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