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Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis

  • Pancreatic Tumors
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusions

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.

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Acknowledgments

Financial Support: NIH T32 CA163177 (TEN, JML), Virginia M. Kincaid Foundation Grant (TWB). The data described were gathered on Caliper IVIS Spectrum funded by the National Institutes of Health Grant (1S10RR025694-01).

Disclosure

The authors disclose no potential conflicts of interest.

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Authors and Affiliations

  1. Department of Surgery, University of Virginia, Charlottesville, VA, USA

    Timothy E. Newhook MD, James M. Lindberg MD, Sara J. Adair MS, Alison J. Kim BA, BS & Todd W. Bauer MD

  2. Department of Pathology, University of Virginia, Charlottesville, VA, USA

    Edward B. Stelow MD

  3. Department of Medicine, Division of Medical Oncology, University of Virginia, Charlottesville, VA, USA

    Osama E. Rahma MD

  4. Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, VA, USA

    J. Thomas Parsons PhD

Authors
  1. Timothy E. Newhook MD
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  2. James M. Lindberg MD
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  3. Sara J. Adair MS
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  4. Alison J. Kim BA, BS
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  5. Edward B. Stelow MD
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  6. Osama E. Rahma MD
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  7. J. Thomas Parsons PhD
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  8. Todd W. Bauer MD
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Corresponding author

Correspondence to Todd W. Bauer MD.

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Newhook, T.E., Lindberg, J.M., Adair, S.J. et al. Adjuvant Trametinib Delays the Outgrowth of Occult Pancreatic Cancer in a Mouse Model of Patient-Derived Liver Metastasis. Ann Surg Oncol 23, 1993–2000 (2016). https://doi.org/10.1245/s10434-016-5116-4

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  • DOI: https://doi.org/10.1245/s10434-016-5116-4

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