What diseases are treated with the combination of dabrafenib and trametinib?

Introduction

Dabrafenib and trametinib are not traditional chemotherapy drugs and have a different way of working. They target the cancer cells to stop them from growing and spreading.

Dabrafenib

Dabrafenib is a BRAF V600E inhibitor that interferes with the RAF/MEK pathway. It is a five-membered heterocyclic group with a central ring locking and affinity for binding BRAF; as a result, there is reversible competitive inhibition of potent adenosine triphosphate, which selectively inhibits the BRAF (V600E) kinase domain. Although BRAF inhibitors could inhibit its target, BRAF V600E inhibitors can only inhibit the mutated BRAF protein, a monomer, rather than the wild-type BRAF dimer. In RAF-mutated cells, activation of MEK/ERK (downstream of RAS/RAF) induces cell survival and proliferation[1]. As a result, negative feedback on MAPK pathway inhibition causes the formation of RAF dimers and insensitivity to RAF inhibitors, which may be the primary cause of drug insensitivity. Targeting multiple MAPK pathway members in CRC can improve the treatment's anti-tumor effect.

Trametinib

Trametinib, an orally administered commercially available MEK inhibitor (MEKi), is currently being investigated in the treatment of surgically inoperable tumors associated with neurofibromatosis type 1 (NF1). It has been approved by the FDA for the treatment of metastatic melanoma[2]. A potential benefit of trametinib for plexiform neurofibromas is suggested by the effectiveness of the MEKi selumetinib in previous studies. The effects of this drug on splicing factor expression have been well-characterized. Trametinib and selumetinib both have the potential to cause cutaneous toxic reactions, most frequently folliculitis eruptions, that can require dosage modifications or drug discontinuation[3].

Uses

Dabrafenib and trametinib are targeted drugs that can be used together to treat melanoma and non-small cell lung cancer. Both drugs are targeted therapy drugs known as cancer growth inhibitors. This treatment is only used if the cancer cells have a change (mutation) in a gene called BRAF. The BRAF gene produces a protein that makes the cancer cells grow. Dabrafenib and trametinib block this protein.

For melanoma skin cancer, you might have dabrafenib and trametinib if the cancer:

cannot be removed with surgery (unresectable)

has spread to other areas of the body (metastatic or advanced melanoma)

It has been completely removed with surgery and is stage 3. You have it after surgery (adjuvant treatment) to reduce the risk of the cancer coming back

For NSCLC, you might have dabrafenib and trametinib if they are your first treatment and the cancer has spread to other areas of the body (advanced or metastatic NSCLC).

You can only have these drugs if your cancer has a BRAF gene change. Open a glossary item (mutation). You have tests on the melanoma and NSCLC cells to check for this gene change before you start treatment.

References

[1] Rana Can Baygin, Ahmet Acar, Kubra Celikbas Yilmaz. “Characterization of dabrafenib-induced drug insensitivity via cellular barcoding and collateral sensitivity to second-line therapeutics.” Scientific Reports 14 1 (2024): 286.

[2] Laura R Bramwell, Lorna W Harries. “Senescence, regulators of alternative splicing and effects of trametinib treatment in progeroid syndromes.” GeroScience (2024): 1861–1879.

[3] Chelsea Steele. “Treatment of Trametinib-Associated Folliculitis Eruption With Fluconazole.” JAMA dermatology 156 6 (2020): 706–708.