{
  "abstract": "Oncogenic mutations in the K-RAS small GTPase occur in more than 90% of human PDACs and cause dysregulation of multiple metabolic pathways, including polyamine metabolism. The goal of this study was to determine whether blocking polyamine synthesis with the irreversible inhibitor α-difluoromethylornithine (DFMO) provides a valid approach to targeting metabolic dependency in mutant K-RAS pancreatic tumors, compared with direct suppression of the oncogenic K-RAS protein. The anti-tumor activity of DFMO was evaluated in vitro and in vivo in the MIA PaCa-2 pancreatic cell line (K-RASG12C) and its isogenic clonally selected line M-27, which does not express a functional GTP-bound RAS protein. MIA PaCa-2 and M-27 cells had comparable intracellular polyamine levels, and DFMO treatment effectively suppressed total polyamine levels in both cell lines (p < 0.01). DFMO reduced the protein levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) and RAS-like small GTPase A (RalA) but induced the phosphoinositide 3-phosphate kinase (PI3K) signaling pathway. Additionally, the intracellular levels of K-RAS and hypusinated eukaryotic initiation factor 5 A (eIF5AHyp) proteins were suppressed in DFMO-treated MIA PaCa-2 cells. DFMO therapy regimen (500 mg/kg/day by oral gavage) significantly improved survival rates of SCID mice with orthotopically implanted MIA PaCa-2 cell line (MIA PaCa-2 control vs. MIA PaCa-2 DFMO, p = 0.0184), with median survival time comparable to animals implanted with M-27 cell line (MIA PaCa-2 control vs. M-27 control, p = 0.0204). DFMO treatment did not significantly improve survival of mice bearing M-27 tumors (M-27 control vs. M-27 DFMO, p = 0.6055). These data indicate that DFMO treatment suppresses pancreatic tumorigenesis driven by the mutant K-RAS oncogene similarly to the targeted elimination of the active GTP-bound RAS protein.",
  "abstract_shown": true,
  "affiliations": [
    "University of Arizona Cancer Center, Tucson, AZ, USA.",
    "Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ, USA.",
    "University of Arizona Cancer Center, Tucson, AZ, USA. nai@arizona.edu.",
    "Department of Cellular & Molecular Medicine, University of Arizona, Tucson, AZ, USA. nai@arizona.edu."
  ],
  "article_type": "research article",
  "arxiv": null,
  "author_total": 5,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "Hwudaurw Chen"
    },
    {
      "affs": [
        0
      ],
      "name": "David E Stringer"
    },
    {
      "affs": [
        0
      ],
      "name": "Haiyan Cui"
    },
    {
      "affs": [
        1
      ],
      "name": "Eugene W Gerner"
    },
    {
      "affs": [
        2,
        3
      ],
      "name": "Natalia A Ignatenko",
      "orcid": "0000-0002-8096-1340"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/fhjwgychwrtcx.bib",
  "cited_by": 0,
  "doi": "10.1007/s00726-026-03559-5",
  "fulltext_url": "https://europepmc.org/articles/PMC13676551",
  "id": "fhjwgychwrtcx",
  "issns": [
    "0939-4451",
    "1438-2199"
  ],
  "landing_url": "https://europepmc.org/article/MED/42892656",
  "language": "eng",
  "licence": "CC-BY",
  "licence_label": "CC BY",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "openalex",
      "1312|Polyamine Metabolism and Applications"
    ]
  ],
  "openalex": "W7213338018",
  "pdf_url": "https://europepmc.org/articles/PMC13676551?pdf=render",
  "pmcid": "PMC13676551",
  "pmid": "42892656",
  "published": "2026-09-16",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/fhjwgychwrtcx.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:19:16Z",
      "native_id": "MED:42892656",
      "source": "europepmc",
      "url": "https://europepmc.org/article/MED/42892656"
    }
  ],
  "subjects": [
    {
      "field": "biochemistry",
      "origin": "openalex:1312|Polyamine Metabolism and Applications",
      "subfield": "molecular-biology"
    }
  ],
  "title": "Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.",
  "title_text": "Difluoromethylornithine modulates mutant K-RAS signaling pathways in pancreatic cancer cells.",
  "type": "peer-reviewed",
  "updated_at": "2026-10-30T12:19:16Z",
  "url": "https://research.draconitic.com/paper/fhjwgychwrtcx",
  "venue": "Amino acids",
  "versions": []
}