Challenges in the treatment of melanoma with BRAF and MEK inhibitors in patients with sickle cell disease: case report and review of the literature

by Selleckchem | Apr 07 2023

Patients with sickle cell disease (SCD) suffer from complications due to anemia, inflammation, and vaso-occlusion. Factors that trigger sickling and/or inflammation may initiate such complications, while treatment with hydroxyurea (HU) reduces their emergence and prolongs survival. On the contrary, inhibition of the BRAF-MEK-ERK pathway with BRAF and MEK inhibitors (BRAF/MEKi) has revolutionized treatment of melanoma but their use has been correlated with inflammatory adverse events. Thus, treatment of patients with SCD with BRAF/MEKi may be quite challenging and pyrexia in those patients should be managed as a medical emergency. In this article, intrigued by the case of a 36-year-old female patient with S/β-thal under HU who was treated with dabrafenib and trametinib for melanoma, we analyze the mechanisms underlying inflammation and vaso-occlusion in SCD, the mechanisms of pyrexia and inflammation induced by BRAF/MEKi, their potential interconnections, the shared role of the inflammasome in these two entities, and the protective effect of HU in SCD. Since SCD is the most common inheritable blood disorder, the administration of BRAF/MEKi for melanoma in patients with SCD may be a rather common challenge. Thus, proper treatment with HU may pave the way for an uneventful management of such patients.

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Sickle cell disease (SCD) is a genetic disorder that affects the shape and function of red blood cells, leading to complications such as anemia, inflammation, and vaso-occlusion. Hydroxyurea (HU) is a treatment that has been shown to reduce the frequency and severity of these complications and improve survival. However, the use of BRAF and MEK inhibitors (BRAF/MEKi) for the treatment of melanoma has been associated with inflammatory adverse events, which may make their use in patients with SCD challenging.

The mechanisms underlying inflammation and vaso-occlusion in SCD involve the activation of various pathways, including the inflammasome, which is a key mediator of the inflammatory response. The inflammasome is a multi-protein complex that activates the production of pro-inflammatory cytokines, leading to inflammation and tissue damage. The activation of the inflammasome in SCD is triggered by a variety of factors, including oxidative stress, hypoxia, and the presence of damaged red blood cells.

BRAF/MEKi act by inhibiting the BRAF-MEK-ERK pathway, which is a key signaling pathway involved in cell proliferation and survival. However, the inhibition of this pathway can also lead to the activation of the inflammasome and the production of pro-inflammatory cytokines. This can result in fever, rash, and other inflammatory adverse events, which may be particularly problematic in patients with SCD.

The use of HU in SCD has been shown to have a protective effect against inflammation and vaso-occlusion. HU works by increasing the production of fetal hemoglobin, which has a different structure than adult hemoglobin and is less likely to sickle. Additionally, HU has been shown to have anti-inflammatory effects and to reduce the production of pro-inflammatory cytokines.

In conclusion, the use of BRAF/MEKi for the treatment of melanoma in patients with SCD may be challenging due to the potential for inflammatory adverse events. Understanding the mechanisms underlying inflammation and vaso-occlusion in SCD and the potential interconnections with the inflammatory effects of BRAF/MEKi may help to guide the management of these patients. The use of HU may be particularly important in reducing the risk of inflammatory adverse events and improving outcomes in patients with SCD.