NEWS ｜ 13 September 2024

WIKIMOLE—Trametinib

By TargetMol

Trametinib is a highly selective MEK inhibitor that blocks the proliferation of tumor cells by inhibiting the key enzymes MEK1/2 in the RAS-RAF-MEK-ERK signaling pathway. It can also activate autophagy and induce apoptosis, playing a crucial role in the treatment of cancers with BRAF mutations. Trametinib is commonly used in research related to the treatment of unresectable or metastatic melanoma with BRAF V600E or V600K mutations.

Mechanism of Action

Trametinib can be divided into three pharmacophores, including the 2-F, 4-I substituted phenyl group, the cyclopropyl ring, and the phenylacetamide group. Crystal structures indicate that Trametinib's binding pocket is formed through the KSR:MEK interaction interface[1], which is critical for understanding the structural function of MEK and the mechanisms of Trametinib resistance.

Fig 1The trametinib binding pocket in MEK extends to the KSR interaction interface.

As a reversible inhibitor of mitogen-activated extracellular signal-regulated kinase 1/2 (MEK1/2), Trametinib inhibits the MEK protein, an upstream regulator of the extracellular signal-related kinase (ERK) pathway, ultimately affecting the MAPK pathway and inhibiting cell proliferation. MEK is a downstream signaling protein of RAS and RAF, which means Trametinib may also be effective against cancers with RAS or RAF mutations.

Application

Research on BRAF V600 Mutation-Positive Melanoma

The combination inhibition of BRAF and MEK has become an important therapeutic option for patients with BRAF V600 mutation-positive melanoma. In the treatment of melanoma, the combination of Dabrafenib and Trametinib has demonstrated higher efficacy compared to the use of Dabrafenib or Vemurafenib alone, while also reducing the incidence of clinical adverse events [4][5].

Fig 2Clinical Trial Results of Dabrafenib/Vemurafenib/Dabrafenib and Trametinib Combination Therapy for Melanoma

Research on the Treatment of Low-Grade Glioma

Low-grade glioma (LGG) is a common primary brain tumor, especially prevalent among younger individuals. Studies have shown that some patients with low-grade glioma harbor the BRAF V600E mutation, offering a new avenue for targeted therapy.

Trametinib can inhibit the MEK-ERK pathway activated by the BRAF mutation, thereby preventing tumor cell proliferation. For pediatric low-grade gliomas (particularly those with the BRAF V600 mutation), Trametinib, either as a monotherapy or in combination with Dabrafenib, has shown promising efficacy and safety. This discovery opens new possibilities for treating pediatric malignant tumors.

Clinical studies have evaluated the efficacy and safety of Trametinib, with or without Dabrafenib, in treating low-grade gliomas with the BRAF V600 mutation. Preliminary data suggests that combination therapy can further enhance efficacy and prolong progression-free survival.

Fig 3Study design

Research on Treatment of BRAF V600 Mutation-Positive Non-Small Cell Lung Cancer

BRAF mutations occur in approximately 1-2% of non-small cell lung cancer (NSCLC) cases, with the V600E mutation being one of the more common types. As an oncogenic driver, this mutation leads to abnormal activation of the RAS-RAF-MEK-ERK signaling pathway, thereby promoting tumor growth and survival.

Fig 4 Percentage of maximum tumor shrinkage in different response types after combined treatment with Dabrafenib and Trametinib

In a recent clinical trial, Dabrafenib, either as a monotherapy or in combination with Trametinib, demonstrated significant anti-tumor activity and manageable safety in patients with previously treated metastatic NSCLC harboring the BRAF V600E mutation (as shown in Figure 5). This combination therapy offers a new treatment option for this patient group [8].

References

[1]Khan ZM,et,al. Structural basis for the action of the drug trametinib at KSR-bound MEK. Nature. 2020 Dec;588(7838):509-514.

[2]Luke JJ, et,al. New developments in the treatment of metastatic melanoma - role of dabrafenib-trametinib combination therapy. Drug Healthc Patient Saf. 2014 Jun 24;6:77-88.

[3]Yamaguchi T, et,al. Antitumor activities of JTP-74057 (GSK1120212), a novel MEK1/2 inhibitor, on colorectal cancer cell lines in vitro and in vivo. Int J Oncol. 2011 Jul;39(1):23-31.

[4]Long GV, et,al. Combined BRAF and MEK inhibition versus BRAF inhibition alone in melanoma. N Engl J Med. 2014 Nov 13;371(20):1877-88.

[5]Lupi C, et,al. Association of BRAF V600E mutation with poor clinicopathological outcomes in 500 consecutive cases of papillary thyroid carcinoma. J Clin Endocrinol Metab. 2007 Nov;92(11):4085-90.

[6]Bouffet E, et,al. Dabrafenib plus Trametinib in Pediatric Glioma with BRAF V600 Mutations. N Engl J Med. 2023 Sep 21;389(12):1108-1120.

[7]Bouffet E,et,al. Efficacy and Safety of Trametinib Monotherapy or in Combination With Dabrafenib in Pediatric BRAF V600-Mutant Low-Grade Glioma. J Clin Oncol. 2023 Jan 20;41(3):664-674.

[8]Planchard D, et,al. Dabrafenib plus trametinib in patients with previously untreated BRAFV600E-mutant metastatic non-small-cell lung cancer: an open-label, phase 2 trial. Lancet Oncol. 2017 Oct;18(10):1307-1316.