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Article

Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer

  • Authors:
    • Douglas W. Ball
    • Ning Jin
    • Ping Xue
    • Sheetal Bhan
    • Shabina R. Ahmed
    • D. Marc Rosen
    • Adam Schayowitz
    • Douglas P. Clark
    • Barry D. Nelkin
  • View Affiliations / Copyright

    Affiliations: Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA, Division of Endocrinology, Metabolism and Diabetes, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA, BioMarker Strategies, Inc., Rockville, MD 20855, USA
  • Pages: 2319-2324
    |
    Published online on: August 26, 2015
       https://doi.org/10.3892/or.2015.4225
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Abstract

Multikinase inhibitors (MKIs) targeting VEGF receptors and other receptor tyrosine kinases have shown considerable activity in clinical trials of thyroid cancer. Thyroid cancer frequently exhibits activation of the RAS/RAF/MEK/ERK pathway. In other types of cancer, paradoxical ERK activation has emerged as a potential resistance mechanism to RAF-inhibiting drugs including MKIs such as sorafenib and pazopanib. We therefore queried whether the MEK inhibitor trametinib, could augment the activity of pazopanib in thyroid cancer cell lines. Trametinib potently inhibited growth in vitro (GI50 1.1-4.8 nM), whereas pazopanib had more limited in vitro activity, as anticipated (GI50 1.4-7.1 µM). We observed progressive upregulation of ERK activity with pazopanib treatment, an effect abrogated by trametinib. For xenografts (bearing either KRASG12R or BRAFV600E mutations), the combination of trametinib and pazopanib led to sustained shrinkage in tumor volume by 50% or more, compared to pre-treatment baseline. Trametinib also was highly effective as a single agent, compared to pazopanib alone. These preclinical findings support the evaluation of trametinib, alone or in combination with pazopanib or other kinase inhibitors, in thyroid cancer clinical trials. We highlight the importance of pharmacodynamic assessment of the ERK pathway for patients enrolled in trials involving MKIs.
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Copy and paste a formatted citation
Spandidos Publications style
Ball DW, Jin N, Xue P, Bhan S, Ahmed SR, Rosen DM, Schayowitz A, Clark DP and Nelkin BD: Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer. Oncol Rep 34: 2319-2324, 2015.
APA
Ball, D.W., Jin, N., Xue, P., Bhan, S., Ahmed, S.R., Rosen, D.M. ... Nelkin, B.D. (2015). Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer. Oncology Reports, 34, 2319-2324. https://doi.org/10.3892/or.2015.4225
MLA
Ball, D. W., Jin, N., Xue, P., Bhan, S., Ahmed, S. R., Rosen, D. M., Schayowitz, A., Clark, D. P., Nelkin, B. D."Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer". Oncology Reports 34.5 (2015): 2319-2324.
Chicago
Ball, D. W., Jin, N., Xue, P., Bhan, S., Ahmed, S. R., Rosen, D. M., Schayowitz, A., Clark, D. P., Nelkin, B. D."Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer". Oncology Reports 34, no. 5 (2015): 2319-2324. https://doi.org/10.3892/or.2015.4225
Copy and paste a formatted citation
x
Spandidos Publications style
Ball DW, Jin N, Xue P, Bhan S, Ahmed SR, Rosen DM, Schayowitz A, Clark DP and Nelkin BD: Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer. Oncol Rep 34: 2319-2324, 2015.
APA
Ball, D.W., Jin, N., Xue, P., Bhan, S., Ahmed, S.R., Rosen, D.M. ... Nelkin, B.D. (2015). Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer. Oncology Reports, 34, 2319-2324. https://doi.org/10.3892/or.2015.4225
MLA
Ball, D. W., Jin, N., Xue, P., Bhan, S., Ahmed, S. R., Rosen, D. M., Schayowitz, A., Clark, D. P., Nelkin, B. D."Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer". Oncology Reports 34.5 (2015): 2319-2324.
Chicago
Ball, D. W., Jin, N., Xue, P., Bhan, S., Ahmed, S. R., Rosen, D. M., Schayowitz, A., Clark, D. P., Nelkin, B. D."Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer". Oncology Reports 34, no. 5 (2015): 2319-2324. https://doi.org/10.3892/or.2015.4225
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