Trametinib 2mg tablets

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 [A7496][A258323] 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.[A7496][A258323] 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.[A7496][A258323] Certain cancers, such as melanoma, are associated with BRAF mutations, with one study suggesting that BRAF is mutated in about 50% of melanoma tumours.[A258323] BRAF V600E and V600K mutations account for 95% of BRAF mutations.[A258298] These BRAF mutations cause constitutive activation of the RAS-RAF-MEK-ERK pathway,[L45558][L45583] leading to dysregulated proliferation and survival of tumour cells.[A258298]

Trametinib is a reversible, highly selective, allosteric inhibitor of MEK1 and MEK2.[L45558][L45583] By binding to unphosphorylated MEK1 and MEK2 with high affinity, trametinib blocks the catalytic activity of MEKs.[A7496][A32984][A258298] It also maintains MEK in an unphosphorylated form, preventing phosphorylation and activation of MEKs.[A7496][A32984][A258298]

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.[A258323] 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.[L45558] 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.[L45583]