Ball Douglas W, Jin Ning, Xue Ping, Bhan Sheetal, Ahmed Shabina R, Rosen D Marc, Schayowitz Adam, Clark Douglas P, Nelkin Barry D
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.
Oncol Rep. 2015 Nov;34(5):2319-24. doi: 10.3892/or.2015.4225. Epub 2015 Aug 26.
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.
靶向血管内皮生长因子（VEGF）受体和其他受体酪氨酸激酶的多激酶抑制剂（MKIs）在甲状腺癌临床试验中已显示出可观的活性。甲状腺癌常表现出RAS/RAF/MEK/ERK通路的激活。在其他类型的癌症中，矛盾的ERK激活已成为对包括索拉非尼和帕唑帕尼等MKIs在内的RAF抑制药物的一种潜在耐药机制。因此，我们探究了MEK抑制剂曲美替尼是否能增强帕唑帕尼在甲状腺癌细胞系中的活性。曲美替尼在体外能有效抑制生长（半数抑制浓度[GI50]为1.1 - 4.8 nM），而正如预期的那样，帕唑帕尼的体外活性较为有限（GI50为1.4 - 7.1 μM）。我们观察到帕唑帕尼治疗后ERK活性逐渐上调，而曲美替尼可消除这种作用。对于异种移植瘤（携带KRASG12R或BRAFV600E突变），与治疗前基线相比，曲美替尼和帕唑帕尼联合使用可使肿瘤体积持续缩小50%或更多。与单独使用帕唑帕尼相比，曲美替尼作为单一药物也非常有效。这些临床前研究结果支持在甲状腺癌临床试验中评估曲美替尼单独使用或与帕唑帕尼或其他激酶抑制剂联合使用的效果。我们强调了对参与MKIs试验的患者进行ERK通路药效学评估的重要性。
