Trametinib

The mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinases (ERK) pathway, also known as the RAS-RAF-MEK-ERK pathway, activates a cascade of cell surface receptors and intracellular downstream signalling molecules. Activated RAS protein activates RAF, a serine/threonine kinase that activates other downstream proteins such as mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2. MEKs then activates ERK, which works on several target proteins and nuclear transcription factors that regulate cell proliferation, differentiation, survival, and growth. ARAF, BRAF, and CRAF are three isoforms of RAF identified in humans. In particular, BRAF is known to be the most critical activator in melanoma. Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours. BRAF V600E and V600K mutations account for 95% of BRAF mutations. These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway, leading to dysregulated proliferation and survival of tumour cells.

Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2. By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs. It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs.

In vitro studies suggest that dual inhibition of the MAPK pathway by MEK and B-RAF inhibitors is associated with a synergistic effect and improved therapeutic efficacy in cancers compared to using either drug alone. The combined use of trametinib and dabrafenib, a BRAF inhibitor, results in more significant growth inhibition of BRAF V600 mutation-positive tumour cell lines in vitro and prolonged inhibition of tumour growth in BRAF V600 mutation-positive tumour xenografts compared to either drug alone. The combined inhibition of MEK by trametinib and RAF by dabrafenib delays the emergence of resistance in vivo in BRAF V600 mutation-positive melanoma xenografts.