Open Access

Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts

  • Authors:
    • Nicholas J. Andersen
    • Elissa B. Boguslawski
    • Cynthia Y. Kuk
    • Christopher M. Chambers
    • Nicholas S. Duesbery
  • View Affiliations

  • Published online on: May 6, 2015     https://doi.org/10.3892/ijo.2015.2989
  • Pages: 71-80
  • Copyright: © Andersen et al. This is an open access article distributed under the terms of Creative Commons Attribution License [CC BY_NC 3.0].

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Abstract

Angiosarcoma (AS) is a rare neoplasm of endothelial origin that has limited treatment options and poor five-year survival. Using tumorgraft models, we previously showed that AS is sensitive to small-molecule inhibitors that target mitogen-activated/extracellular-signal-regulated protein kinase kinases 1 and 2 (MEK). The objective of this study was to identify drugs that combine with MEK inhibitors to more effectively inhibit AS growth. We examined the in vitro synergy between the MEK inhibitor PD0325901 and inhibitors of eleven common cancer pathways in melanoma cell lines and canine angiosarcoma cell isolates. Combination indices were calculated using the Chou-Talalay method. Optimized combination therapies were evaluated in vivo for toxicity and efficacy using canine angiosarcoma tumorgrafts. Among the drugs we tested, rapamycin stood out because it showed strong synergy with PD0325901 at nanomolar concentrations. We observed that angiosarcomas are insensitive to mTOR inhibition. However, treatment with nanomolar levels of mTOR inhibitor renders these cells as sensitive to MEK inhibition as a melanoma cell line with mutant BRAF. Similar results were observed in B-Raf wild-type melanoma cells as well as in vivo, where treatment of canine AS tumorgrafts with MEK and mTOR inhibitors was more effective than monotherapy. Our data show that a low dose of an mTOR inhibitor can dramatically enhance angiosarcoma and melanoma response to MEK inhibition, potentially widening the field of applications for MEK-targeted therapy.
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July-2015
Volume 47 Issue 1

Print ISSN: 1019-6439
Online ISSN:1791-2423

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Spandidos Publications style
Andersen NJ, Boguslawski EB, Kuk CY, Chambers CM and Duesbery NS: Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts. Int J Oncol 47: 71-80, 2015
APA
Andersen, N.J., Boguslawski, E.B., Kuk, C.Y., Chambers, C.M., & Duesbery, N.S. (2015). Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts. International Journal of Oncology, 47, 71-80. https://doi.org/10.3892/ijo.2015.2989
MLA
Andersen, N. J., Boguslawski, E. B., Kuk, C. Y., Chambers, C. M., Duesbery, N. S."Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts". International Journal of Oncology 47.1 (2015): 71-80.
Chicago
Andersen, N. J., Boguslawski, E. B., Kuk, C. Y., Chambers, C. M., Duesbery, N. S."Combined inhibition of MEK and mTOR has a synergic effect on angiosarcoma tumorgrafts". International Journal of Oncology 47, no. 1 (2015): 71-80. https://doi.org/10.3892/ijo.2015.2989