MEK Inhibitor Mechanism of Action, Side Effects, and Uses

Metastatic melanoma is a deadly cancer for which conventional chemotherapy provides little benefit. However, newer therapies involving a pathway called the mitogen-activated protein kinase (MAPK) pathway have demonstrated success in inducing remission.

The MAPK pathway is more accurately termed the RAS-RAF-MEK-ERK pathway, and involves the regulation of cell proliferation and survival. It is constitutionally overactive in 30% of cancers. Two enzymes in this pathway, namely, BRAF and MEK, are target kinases which play crucial roles in the cell cycle.

The first therapies to target this pathway were BRAF inhibitors, but intrinsic and acquired tumor resistance quickly led to treatment failure by reactivation of the MAPK pathway. MEK inhibitors have emerged to partially overcome these resistance mechanisms and are now used in combination with BRAF inhibitors to extend the time to resistance.

MEK is a dual specificity threonine/tyrosine kinase, so called from the term MAPK/ERK kinase. It is a key effector of the three-layered RAS/RAF/MEK/ERK signaling cascade, expressed by seven genes from MAPK1 to MAPK7.

MEK inhibitors bind to and inhibit MEK, inhibiting MEK-dependent cell signaling. This inhibition leads to cell death and the inhibition of tumor growth. These are allosteric binding inhibitors of MEK which inhibit either MEK1 alone, or both MEK1 and MEK2.

What is the mechanism of action of MEK inhibitors?

The MAPK pathway is an intracellular signaling cascade that is involved in the proliferation and survival of tumor cells. Many mutations cause cancer development by activating this pathway, including BRAF and NRAS mutations. MEK is a downstream protein kinase which can be targeted to prevent reactivation of the MAPK pathway in the presence of BRAF or RAS mutations.

Normally, ERK1/2 activation initiates a variety of cellular and nuclear pathways, while also inhibiting Raf activity by a feedback loop to modulate the activity of the MAPK pathway. MEK1/2 inhibition inactivates ERK1/2 and also removes the feedback inhibition on Raf.

Drugs which selectively inhibit the MEK enzymes are able to inhibit growth and to induce the death of cells in the presence of these mutations.

Thus, MEK1/2 is highly selective in inactivating ERK1/2 but leaves other signaling pathways intact. In addition, the non-ATP binding site means they do not typically need to compete with ATP, which is present in very large amounts inside cells. A new ATP-competitive inhibitor has also been designed which is effective in mutants that display drug resistance to the ATP-noncompetitive inhibitors.

The advantages of using combination MEK inhibitor therapy with a BRAF inhibitor is the increased progression-free survival and lower toxicity, when compared with the latter alone.