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  • Writer's pictureDr Edin Hamzić

🧬 💊 Trametinib and the BRAF Gene

Updated: Jan 22

🧬 What Is the BRAF Gene?

  • ⚠️ The BRAF gene encodes an enzyme that belongs to the RAF family of serine/threonine kinases. The BRAF gene is a B homolog within the family of the three Raf genes:

  1. ARAF (A-RAF)

  2. BRAF (B-RAF)

  3. c-RAF (or RAF1)

  • Serine/threonine kinases are enzymes that facilitate the transfer of a phosphate group (generally known as the phosphorylation process).

  • In the case of the BRAF gene, the serine/threonine kinase that the BRAF gene encodes is involved in the processes of regulating the MAP kinase/ERK pathway, and mutations in the BRAF gene have been associated with cancers such as:

  1. Lung adenocarcinoma

  2. Cardiofaciocutaneous syndrome

  3. Colorectal cancer

  4. Leopard syndrome (Noonan syndrome with multiple lentigines (NSML))

  5. Malignant melanoma

  6. Non-small cell lung cancer

  7. Noonan syndrome.

  • ⚠️ Mutations in the BRAF gene can be inherited or caused by environmental factors.

  • ⚠️ The BRAF gene mutation that is well described and investigated in scientific literature is the V600E mutation, where Valine (V) is substituted by glutamic acid (E) at amino acid residue 600.

  • ⚠️ BRAF V600E mutation is found to be a causative agent of over 50% of malignant melanoma cases.

🧬 What is the effect of the BRAF V600E mutation?

  • The BRAF V600E mutation may increase the activity of the BRAF gene, which further affects the growth and spread of cancer cells making the BRAF gene an oncogene.

  • Checking for the V600E BRAF mutation in tumor tissue can help plan cancer treatment.

  • If you are interested in reading more about the BRAF gene, you can check out my article about the BRAF gene here.

💊 What is Trametinib? How does Trametinib work?

  • ⚠️ Trametinib (trade name Mekinist & Meqsel) is a cancer drug. Trametinib is a reversible, allosteric inhibitor of mitogen-activated extracellular signal-regulated kinase 1 (MEK1) and MEK2 activation and MEK1 and MEK2 kinase activity.

  • Shortly, Trametinib is an MEK inhibitor with an anti-cancer activity that is used in combination with dabrafenib to treat adult patients with advanced non-small-cell lung cancer with a BRAF V600 mutation.

  • Trametinib had good results for metastatic melanoma carrying the BRAF V600E mutation.

💊 What Type of Drugs Are MEK Inhibitors?

  • ⚠️ As we mentioned above, Trametinib is a MEK inhibitor.

  • ⚠️ The MEK inhibitors are classified as a new class of chemotherapeutic agents.

  • Up to now, four MEK inhibitors have been approved by FDA, and these are:

  1. Trametinib [citation]

  2. Selumetinib [citation]

  3. Binimetinib [citation]

  4. Cobimetinib [citation]

  • ⚠️ Notably, trametinib is the only MEK inhibitor approved for treating NSCLC patients with BRAF V600E mutation in combination with dabrafenib until now [citation].

🤖How do MEK inhibitors work? What is Dabrafenib and Trametinib?

  • ℹ️ MEK proteins are upstream regulators of the extracellular signal-related kinase (ERK) pathway, promoting cellular proliferation. MEK inhibitors are drugs that block mitogen-activated protein kinases MEK1 and MEK2. Since these kinases are involved in the MEK/ERK signaling pathway, MEK inhibitors work by suppressing the pathway activity.

  • ℹ️ In the context of BRAF mutations, MEK inhibitors can be used to treat BRAF-positive tumors, as they suppress the effect of BRAF mutation that causes the MEK/ERK pathway to becoming overly active.

🔗 How Trametinib and the BRAF gene are related?

  • ⚠️ Trametinib helps with melanoma with the BRAF V600E or V600K as the mutation results in the constitutive activation of the BRAF pathway, which includes MEK1 and MEK2.

  • ⚠️ Dabrafenib is a drug (chemical) that acts as an inhibitor of the associated enzyme B-Raf. Trametinib is a MEK inhibitor drug that inhibits MEK1 and MEK2 kinases.

🏭 Who manufactures trametinib? How is trametinib taken? How do you dissolve trametinib?

  • Originally, GlaxoSmithKline (GSK) developed and marketed trametinib, but back in 2015, Novartis acquired GlaxoSmithKline’s oncology portfolio, and trametinib is considered to be developed by Novartis. Trametinib is

  • Trametinib comes as a tablet to take by mouth. It is usually taken once a day on an empty stomach, at least 1 hour before or 2 hours after a meal. Still, the dose might be adjusted depending on the response to treatment and any side effects one eventually experiences [citation].

  • A stock solution may be made by dissolving the trametinib in the solvent of choice. Trametinib is soluble in organic solvents such as DMSO and dimethylformamide, which should be purged with inert gas. The solubility in these solvents is approximately 3 and 2 mg/ml, respectively. Trametinib is sparingly soluble in aqueous buffers. For maximum solubility in aqueous buffers, trametinib should first be dissolved in DMSO and then diluted with an aqueous buffer. Trametinib has a solubility of approximately 0.3 mg/ml in 1:2 solution of DMSO: PBS (pH 7.2 using this method) [citation].


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