Trametinib with and without pazopanib has potent preclinical activity in thyroid cancer
Douglas W Ball1, Ning Jin1, Ping Xue1
1Cancer Biology Division, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, MD 21287, USA.
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.
Insights
The MEK inhibitor trametinib combined with pazopanib significantly reduced thyroid cancer tumor growth in preclinical models. This combination therapy, along with monitoring the ERK pathway, shows promise for future thyroid cancer clinical trials.
Area of Science:
- Oncology
- Molecular Biology
- Pharmacology
Background:
- Multikinase inhibitors (MKIs) targeting VEGF receptors demonstrate activity in thyroid cancer.
- Thyroid cancer often involves RAS/RAF/MEK/ERK pathway activation.
- Paradoxical ERK activation can be a resistance mechanism to RAF inhibitors like sorafenib and pazopanib.
Purpose of the Study:
- To investigate if the MEK inhibitor trametinib can enhance pazopanib's efficacy in thyroid cancer.
- To evaluate the combination of trametinib and pazopanib in preclinical thyroid cancer models.
Main Methods:
- In vitro cell line growth inhibition assays (GI50) for trametinib and pazopanib.
- Assessment of ERK pathway activity following pazopanib treatment, with and without trametinib.
- In vivo xenograft studies in mice bearing KRASG12R or BRAFV600E mutations to evaluate tumor volume changes.
Main Results:
- Trametinib showed potent in vitro activity (GI50 1.1-4.8 nM), while pazopanib had limited activity (GI50 1.4-7.1 µM).
- Pazopanib treatment increased ERK activity, which was blocked by trametinib.
- The combination of trametinib and pazopanib induced significant tumor shrinkage (≥50%) in xenografts.
- Trametinib as a single agent was also highly effective compared to pazopanib alone.
Conclusions:
- Preclinical data support evaluating trametinib, alone or with pazopanib/other kinase inhibitors, in thyroid cancer clinical trials.
- Pharmacodynamic monitoring of the ERK pathway is crucial for patients in MKI trials.
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