Trametinib

Brand Name: Mekinist

Trametinib is used to treat unresectable or metastatic melanoma with BRAF V600E or V600K mutations. Trametinib is also used in combination with dabrafenib for various types of cancer with BRAF V600E or V600K mutations, including metastatic non-small cell lung cancer, locally advanced or metastatic anaplastic thyroid cancer, and low-grade glioma.1

How Does Trametinib Work?

A diagram of the RAS pathway with a step-wise chain of activation starting from input growth signal, RAS, RAF, MEK, ERK, to output growth signal.

The RAS signaling pathway is a key regulator of cellular growth and the dysfunction of this pathway is implicated in many diseases, including cancer. The RAS pathway begins with a protein called RAS, which is activated by integrating growth signals from variety of sources. This results in a step-wise activation of downstream proteins: (1) active RAS activates RAF, (2) active RAF activates MEK, and (3) active MEK activates ERK. Active ERK then outputs growth signal to regulate diverse aspects of cellular growth.2

A diagram comparing the normal RAS pathway to the BRAF V600E mutated RAS pathway, both in the absence of input growth signal. There is no output growth signal in the normal pathway, but there is a strong output growth signal in the mutated pathway.

In the absence of input growth signal, which is typical for many cells, RAS, and the pathway as a whole, remains inactive. However, some cancer cells possess a BRAF mutation called V600E, which activates BRAF even without active RAS. Because this results in constitutively active output growth signal via ERK, cancer cells with this mutation can grow uncontrollably.3

A diagram of the BRAF V600E mutated RAS pathway with BRAF blocked by a BRAF inhibitor. There is no output growth signal.

Cancers with BRAF V600E mutation are often treated with a BRAF inhibitor, such as dabrafenib4 and vemurafenib5, which specifically inactivates mutated BRAF. This turns off the output growth signal, and as a result, cancer growth is halted.

A diagram of the BRAF V600E mutated RAS pathway with BRAF blocked by a BRAF inhibitor. An alternate pathway feeds into MEK, and there is a strong output growth signal.

However, over time, cancer cells develop resistance to BRAF inhibitors by bypassing BRAF and directly activating MEK.6 This again results in a constitutively active output signal.

A diagram of the BRAF V600E mutated RAS pathway with BRAF blocked by a BRAF inhibitor and MEK blocked by a MEK inhibitor. There is no output growth signal.

Trametinib is a drug that inhibits MEK.7 It is often used in combination with BRAF inhibitor dabrafenib8 to more effectively shut down the RAS pathway and limit drug resistance from developing.9,10 This again turns off the output growth signal, and as a result, cancer growth is halted.

References

1. MEKINIST. U.S. Food and Drug Administration (2023).

2. Seger, R. & Krebs, E. G. The MAPK signaling cascade. The FASEB Journal 9, 726-735 (1995).

3. Davies, H. et al. Mutations of the BRAF gene in human cancer. Nature 417, 949-954 (2002).

4. Hauschild, A. et al. Dabrafenib in BRAF-mutated metastatic melanoma: a multicentre, open-label, phase 3 randomised controlled trial. The Lancet 380, 358-365 (2012).

5. Chapman, P. B. et al. Improved Survival with Vemurafenib in Melanoma with BRAF V600E Mutation. The New England Journal of Medicine 364, 2507-2516 (2011).

6. Villanueva, J., Vultur, A. & Herlyn, M. Resistance to BRAF Inhibitors: Unraveling Mechanisms and Future Treatment Options. Cancer Research 71, 7137-7140 (2011).

7. Gilmartin, A. G. et al. GSK1120212 (JTP-74057) Is an Inhibitor of MEK Activity and Activation with Favorable Pharmacokinetic Properties for Sustained In Vivo Pathway Inhibition. Clinical Cancer Research 17, 989-1000 (2011).

8. Gouda, M. A. & Subbiah, V. Expanding the Benefit: Dabrafenib/Trametinib as Tissue-Agnostic Therapy for BRAF V600E-Positive Adult and Pediatric Solid Tumors. American Society of Clinical Oncology Educational Book 43, e404770 (2023).

9. King, A. J. et al. Dabrafenib; Preclinical Characterization, Increased Efficacy when Combined with Trametinib, while BRAF/MEK Tool Combination Reduced Skin Lesions. PLoS ONE 8, e67583 (2013).

10. Long, G. V. et al. Combined BRAF and MEK Inhibition versus BRAF Inhibition Alone in Melanoma. The New England Journal of Medicine 371, 1877-1888 (2014).