ArticleAnnals of surgical oncology2016
Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis.
Article in Annals of surgical oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 10 papers.
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Who cites it
10 citing papers in PubMed, 14 citations in OpenAlex.
- PTEN Oxidation Promotes Constitutive PI3K Signaling and Inducible Macropinocytosis in Pancreatic Cancer.Cancer research · 2026Article
- KRASG12R-Mutant Pancreatic Cancer Features Limited ERK/MAPK Transcriptional Activity and a Distinctive Tumor Microenvironment.Cancer research · 2026Article
- The kinase ERK plays a conserved dominant role in the heterogeneity of epithelial-mesenchymal transition in pancreatic cancer cells.Science signaling · 2025Article
- PRMT5 Identified as a Viable Target for Combination Therapy in Preclinical Models of Pancreatic Cancer.Biomolecules · 2025Article
- Preclinical evidence for employing MEK inhibition in NRAS mutated pediatric gastroenteropancreatic neuroendocrine-like tumors.Translational oncology · 2024Article
- Newly developed preclinical models reveal broad-spectrum CDK inhibitors as potent drugs for CRPC exhibiting primary resistance to enzalutamide.Cancer science · 2024Article
- Patient-Derived Tumor Xenografts Plus Ex Vivo Models Enable Drug Validation for Tenosynovial Giant Cell Tumors.Annals of surgical oncology · 2021Article
- Electrophysiology-based stratification of pancreatic tumorigenicity by label-free single-cell impedance cytometry.Analytica chimica acta · 2020Article
- CD47 Blockade as an Adjuvant Immunotherapy for Resectable Pancreatic Cancer.Clinical cancer research : an official journal of the American Association for Cancer Research · 2018Article
- Inhibition of the MEK/ERK pathway augments nab-paclitaxel-based chemotherapy effects in preclinical models of pancreatic cancer.Oncotarget · 2018Article
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Authors and funding
8 authors at 1 institution in 1 country.
Funding
Abstract
purposeMost 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.
methodsLiver 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.
resultsTrametinib (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.
conclusionsTreatment 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.
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