title: Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis.
abstract: Most patients with pancreatic ductal adenocarcinoma (PDAC) die within 5 years following resection plus adjuvant gemcitabine (Gem) from outgrowth of occult metastases. We hypothesized that inhibition of the KRAS pathway with the MEK inhibitor trametinib would inhibit the outgrowth of occult liver metastases in a preclinical model.
  
  
  
  Liver metastases harvested from two patients with PDAC (Tumors 608, 366) were implanted orthotopically in mice. Tumor cell lines were derived and transduced with lentiviruses encoding luciferase and injected into spleens of mice generating microscopic liver metastases. Growth kinetics of liver metastases were measured with bioluminescent imaging and time-to-progression (TTP), progression-free survival (PFS), and overall survival (OS) were determined.
  
  
  
  Trametinib (0.3 mg/kg BID) significantly prolonged OS versus control (Tumor 608: 114 vs. 43 days, p < 0.001; Tumor 366: not reached vs. 167 days, p = 0.0488). In vivo target validation demonstrated trametinib significantly reduced phosphorylated-ERK and expression of the ERK-responsive gene DUSP6. In a randomized, preclinical trial, mice were randomized to: (1) control, (2) adjuvant Gem (100 mg/kg IP, Q3 days) × 7 days followed by surveillance, or (3) adjuvant Gem followed by trametinib. Sequential Gem-trametinib significantly decreased metastatic cell outgrowth and increased TTP and PFS.
  
  
  
  Treatment of mice bearing micrometastases with trametinib significantly delayed tumor outgrowth by effectively inhibiting KRAS-MEK-ERK signaling. In a randomized, preclinical, murine trial adjuvant sequential Gem followed by trametinib inhibited occult metastatic cell outgrowth in the liver and increased PFS versus adjuvant Gem alone. An adjuvant trial of sequential Gem-trametinib is being planned in patients with resected PDAC.
authors: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors: Timothy E
authors: TE
authors: Newhook
authors: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors: James M
authors: JM
authors: Lindberg
authors: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors: Sara J
authors: SJ
authors: Adair
authors: Department of Surgery, University of Virginia, Charlottesville, VA, USA.
authors: Alison J
authors: AJ
authors: Kim
authors: Department of Pathology, University of Virginia, Charlottesville, VA, USA.
authors: Edward B
authors: EB
authors: Stelow
authors: Department of Medicine, Division of Medical Oncology, University of Virginia, Charlottesville, VA, USA.
authors: Osama E
authors: OE
authors: Rahma
authors: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA.
authors: J Thomas
authors: JT
authors: Parsons
authors: Department of Surgery, University of Virginia, Charlottesville, VA, USA. twb7f@virginia.edu.
authors: Todd W
authors: TW
authors: Bauer
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000517:prevention & control* / Q000556:secondary; D006801:Humans; D008113:Liver Neoplasms / Q000517:prevention & control* / Q000556:secondary; D051379:Mice; D010190:Pancreatic Neoplasms / Q000473:pathology / Q000517:prevention & control*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011728:Pyridones / Q000494:pharmacology*; D011744:Pyrimidinones / Q000494:pharmacology*; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D047428:Protein Kinase Inhibitors; D011728:Pyridones; D011744:Pyrimidinones; C560077:trametinib