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

Oncology Reports
Douglas W BallBarry D Nelkin

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...Continue Reading

References

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Citations

Oct 26, 2018·Molecular Cancer·Shikha SainiBellur S Prabhakar
Jul 5, 2019·International Journal of Molecular Sciences·Livia ManzellaPaolo Vigneri
Apr 6, 2017·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Vivek SubbiahNilofer A Azad
Jun 13, 2019·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Razelle KurzrockNilofer S Azad
Aug 3, 2021·Frontiers in Endocrinology·Tanner FullmerMark Zafereo

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Methods Mentioned

BETA
scraping
xenografts
xenograft

Clinical Trials Mentioned

NCT01438554

Software Mentioned

GraphPad Prism
Nikon

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Cell Signaling by Tyrosine Kinases

Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. RTKs have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Discover the latest research on cell signaling and RTK here.

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