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J Invest Dermatol. 2019 May 3. pii: S0022-202X(19)31499-X. doi: 10.1016/j.jid.2019.03.1156. [Epub ahead of print]

Local inhibition of MEK/AKT prevents cellular growth in human congenital melanocytic nevi.

Author information

1
Saint-Antoine Research Center, INSERM UMR_S 938, Paris, France; Sorbonne Université, Paris, France.
2
Saint-Antoine Research Center, INSERM UMR_S 938, Paris, France; Université Paris-Descartes, Paris, France; AP-HP, Hôpital Cochin, Department of Dermatology, Paris, France.
3
Université Paris-Descartes, Paris, France; AP-HP, Hôpital Necker-Enfants-Malades, Department of Maxillofacial and Plastic Surgery, Paris, France.
4
AP-HP, Hôpital Necker-Enfants-Malades, Department of Pathology, Paris, France.
5
Laboratory for Functional Genomics, Fondation Jean Dausset - CEPH, Paris, France.
6
Université Paris-Descartes, Paris, France; AP-HP, Hôpital Européen Georges Pompidou, Department of Plastic Surgery, Paris, France.
7
AP-HP, Hôpital Tenon, Department of Pathology, Paris, France.
8
Saint-Antoine Research Center, INSERM UMR_S 938, Paris, France; Université Paris-Descartes, Paris, France; AP-HP, Hôpital Cochin, Department of Dermatology, Paris, France. Electronic address: sarah.guegan.bart@gmail.com.

Abstract

Large congenital melanocytic nevi (lCMN) management is based exclusively on iterative surgical procedures in the absence of validated medical therapy. The aim of our study was to develop an intra-lesional medical treatment for lCMN. Seventeen patients harboring NRAS-mutated lCMN were included. Nevocytes obtained from lCMN displayed an overactivation of MAPK and AKT pathways. MEK and AKT inhibitors reduced nevosphere diameter in sphere-forming assays, as well as cell viability and proliferation in in vitro assays. Standardized lCMN explants were then cultured ex vivo with the same inhibitors which induced a decrease in MelanA+ and Sox10+ cells in both epidermis and dermis. Finally, intradermal injections of these inhibitors were performed within standardized lCMN xenografts in Rag2-/- mice. They induced a dramatic decrease in nevocytes in treated xenografts which persisted 30 days after the end of treatment. Using original nevus explant and xenograft preclinical models, we demonstrated that intradermal MEK/AKT inhibition might serve as neo-adjuvant therapy for the treatment of NRAS-mutated CMN to avoid iterative surgeries.

PMID:
31059696
DOI:
10.1016/j.jid.2019.03.1156

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