Unbalancing cAMP and Ras/MAPK pathways as a therapeutic strategy for cutaneous neurofibromas

• DOI: 10.1172/jci.insight.168826
• Publication Date: 2024-01-04T17:00:18Z
• Authors: Helena Mazuelas; Miriam Magallón-L...; Itziar Uriarte-Ar...; Alejandro Negro; Inma Rosas; Ignacio Blanco; Elisabeth Castell...; Conxi Lázaro; Bernat Gel; Meritxell Carrió; Eduard Serra
• Keywords: Selumetinib; Crosstalk

Cutaneous neurofibromas (cNFs) are benign Schwann cell (SC) tumors arising from subepidermal glia. Neurofibromatosis Type 1 (NF1) individuals may develop thousands of cNFs, greatly affecting their quality life. cNF growth is driven by the proliferation NF1(-/-) SCs and interaction with NF1(+/-) microenvironment. We analyzed crosstalk between human cNF-derived fibroblasts (FBs), identifying an expression signature specific to SC-FB interaction. validated secretion proteins involved in immune migration, suggesting a role recruitment. The also captured components developmental signaling pathways, including cAMP-elevator G protein-coupled receptor 68 (GPR68). Activation Gpr68 Ogerin combination MEKi Selumetinib reduced viability induced differentiation death primary SCs, result corroborated using iPSC-derived 3D neurofibromasphere model. Similar results were obtained other activators or cAMP analogs/adenylyl cyclase Selumetinib. Interestingly, whereas SC cultures reset after removal single Selumetib treatment, Ogerin-Selumetinib combo elicited permanent halt on expansion, drug removal. These indicate that unbalancing Ras pathways combining elevators arises as potential treatment for cNFs.