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

Ball,Douglas  W.; Jin,Ning; Xue,Ping; Bhan,Sheetal; Ahmed,Shabina R.; Rosen,D.  Marc; Schayowitz,Adam; Clark,Douglas  P.; Nelkin,Barry  D.

doi:10.3892/or.2015.4225

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
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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
Published online on: August 26, 2015 https://doi.org/10.3892/or.2015.4225
Pages: 2319-2324

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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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