Acute Inhibition of MEK Suppresses Congenital Melanocytic Nevus Syndrome in a Murine Model Driven by Activated NRAS and Wnt Signaling

Abstract

Given that psoriasis is increasingly recognized to be associated with comorbid conditions of obesity, diabetes, metabolic dysregulation, and cardiovascular diseases that may be related to inflammation in skin (Davidovici et al., 2010), it is of interest that associated functional pathways were also identified through IPA, including metabolic disease and cardiovascular disease (Supplementary Figure S1b online), leading to two potential mechanisms for increased association between psoriasis and metabolic and cardiovascular comorbidities.First, a product made in psoriatic plaques could produce diffusible hormone-like proteins that influence the biology of distant cells/tissues (e.g., renin, vascular endothelial growth factor, and monocyte chemoattractant 9 protein-1 (CCL2); Table 4) and IL-17 A (Supplementary Figure S2 online). MATERIALS AND METHODS Serum protein profilingA 92-protein vendor-defined multiplex Luminex-based panel (Human Map 1.6 plus IL-17 and IL-23; Rules Based Medicine, Austin, TX) was used to profile differential serum protein expression from healthy volunteers (n = 162) and patients with psoriasis (n = 149). The complete list of analytes in the Human Map 1.6 can be found at http://rulesbasedmedicine.com/products-services/humanmap-services/human-discoverymap.A more sensitive immunoassay, an IL-17A single-plex assay (Singulex, CA) was used to quantify IL-17A in serum from healthy and psoriatic subjects (n = 10 in each group).

Melanoma in congenital melanocytic naevi

“…Animal model data of mitogen-activated protein kinase kinase (MEK) inhibitor use has recently demonstrated an attenuation of leptomeningeal disease in a murine model of CMN syndrome. 46 As a result we have used the MEK inhibitor trametinib as therapy in a small series of four patients with NRAS-mutated CNS melanoma (three of whom had CMN). 47 This demonstrated measurable and objective relief of symptoms and signs in all patients, although to varying degrees.…”

Can Combination MEK and Akt Inhibition Slay the Giant Congenital Nevus?

“…Based on these data, they proposed a new lgCMN management strategy involving the use of injection-based targeted therapies to treat unresectable lesions and reduce lgCMN burden prior to surgery. In support of the therapeutic strategy put forth by Rouille et al 2019, Pawlikowski et al showed that the MEK inhibitor, selumetinib, can limit the extent of cutaneous and central nervous system disease in an NRASmutant, Apc-null CMN mouse model (Pawlikowski et al, 2015). Early clinical data also suggest a role for MEK inhibitors in controlling human lgCMN.…”

“…In the first model, the melanocytic expression of NRas 12D leads to leptomeningeal hyperpigmentation and subsequent melanoma formation (Pedersen et al, 2013). In the second model, the expression of NRas 61R , in combination with activated WNT signaling (Apc loss), causes the mice to develop leptomeningeal melanosis (Pawlikowski et al, 2015). Still, whether the cutaneous and central nervous system lesions that develop in these models fully recapitulate the genetic and pathological heterogeneity of human CMN remains unclear.…”

A mutation in the Cdon gene potentiates congenital nevus development mediated by NRASQ61K

“…transgenic mice carrying melanocyte-specific oncogenic mutations develop dermal melanocytic proliferations reminiscent of human congenital or blue nevi (e.g. Dhomen et al, 2009;Pawlikowski et al, 2015;Shakhova et al, 2012). The development and size of these lesions can be dramatically altered with genetic engineering that results in changes in expression of stem cell or hepatocyte growth factor from keratinocytes (Kunisada et al, 1998(Kunisada et al, , 2000 or increased Wnt signaling within melanocytes (Pawlikowski et al, 2013).…”