In this article, we will discuss Trametinib (Mechanism of Action). So, let’s get started.
Mechanism of Action
Trametinib is a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and
MEK2 activation and of MEK1 and MEK2 kinase activity. MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, which promotes cellular proliferation. BRAF V600E mutations result in constitutive activation of the BRAF pathway which includes MEK1 and MEK2. Trametinib inhibits cell growth of various BRAF V600 mutation-positive tumors in vitro and in vivo.
Trametinib and dabrafenib target two different kinases in the RAS/RAF/MEK/ERK pathway. Use of trametinib and dabrafenib in combination resulted in greater growth inhibition of BRAF V600 mutation-positive tumor cell lines in vitro and prolonged inhibition of tumor growth in BRAF V600 mutation positive tumor xenografts compared with either drug alone.
Administration of 1 mg and 2 mg Trametinib to patients with BRAF V600 mutation-positive melanoma resulted in dose-dependent changes in tumor biomarkers including inhibition of phosphorylated ERK, inhibition
of Ki67 (a marker of cell proliferation), and increases in p27 (a marker of apoptosis).
The heart rate-corrected QT (QTc) prolongation potential of trametinib was assessed in a dedicated study in 32
patients who received placebo on day 1 and Trametinib 2 mg once daily on days 2-14 followed by Trametinib 3 mg on day 15. No clinically relevant QTc prolongation was detected in the study. In clinical trials in patients receiving Trametinib with dabrafenib, QTc prolongation > 500 ms occurred in 0.8% of patients and QTc increased by > 60 ms from baseline in 3.8% of patients.