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  • Genomic and transcriptomic analyses of NF1-mutant melanoma identify potential targeted approach for treatment.

Genomic and transcriptomic analyses of NF1-mutant melanoma identify potential targeted approach for treatment.

The Journal of investigative dermatology (2022-08-22)
George Jour, Irineu Illa-Bochaca, Milad Ibrahim, Douglas Donnelly, Kelsey Zhu, Eleazar Vega-Saenz de Miera, Varshini Vasudevaraja, Valeria Mezzano, Sitharam Ramswami, Yu-Hsin Yeh, Carolyn Winskill, Rebecca A Betensky, Janice Mehnert, Iman Osman
ABSTRACT

There is currently no targeted therapy to treat NF1-mutant melanomas. Herein, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1-WT melanoma to reveal potential treatment targets for this subset of patients. Genomic alterations were verified using qPCR, and differentially expressed genes were independently validated using TCGA data, and immunohistochemistry (IHC). Digital spatial profiling (DSP) with multiplex IHC and immunofluorescence (IF) were used to validate the signatures. The efficacy of combinational regimens driven by these signatures was tested through in vitro assays using low-passage cell lines. Pathogenic NF1 mutations were identified in 27% cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 compared to NF1-WT (P=0.008), which was independently validated both in the TCGA dataset (P=0.01, P=0.03) and with IHC (P=0.013, P=0.036), respectively. DSP analysis showed upregulation of LY6E within the tumor cells [FDR<0.01, lg2FC>1], confirmed with multiplex IF showing co-localization of LY6E in melanoma cells. The combination of MEK and CDC20 co-inhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-MUT cell lines. In conclusion, NF1-mutant melanoma is associated with a distinct genomic and transcriptomic profile. Our data support investigating CDC20 inhibition with MAPK pathway inhibitors as a targeted regimen in this melanoma subtype.

MATERIALS
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Sigma-Aldrich
Anti-NF1 antibody produced in rabbit, Prestige Antibodies® Powered by Atlas Antibodies, affinity isolated antibody, buffered aqueous glycerol solution