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Published on: August 25, 2021
Genomic and Transcriptomic Analyses of NF1-Mutant Melanoma Identify Potential Targeted Approach for Treatment
George Jour1, Irineu Illa-Bochaca2, Milad Ibrahim2
1The Ronald O. Perelman Department of Dermatology, New York University School of Medicine, New York, New York, USA; Department of Pathology, Molecular Pathology and Diagnostics, NYU Langone Medical Center, New York, New York, USA.
Abstract:
There is currently no targeted therapy to treat NF1-mutant melanomas. In this study, we compared the genomic and transcriptomic signatures of NF1-mutant and NF1 wild-type 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 The Cancer Genome Atlas data and immunohistochemistry. Digital spatial profiling with multiplex immunohistochemistry and immunofluorescence 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% of cases. NF1-mutant melanoma expressed higher proliferative markers MK167 and CDC20 than NF1 wild-type (P = 0.008), which was independently validated both in The Cancer Genome Atlas dataset (P = 0.01, P = 0.03) and with immunohistochemistry (P = 0.013, P = 0.036), respectively. Digital spatial profiling analysis showed upregulation of LY6E within the tumor cells (false discovery rate < 0.01, log2 fold change > 1), confirmed with multiplex immunofluorescence showing colocalization of LY6E in melanoma cells. The combination of MAPK/extracellular signal‒regulated kinase kinase and CDC20 coinhibition induced both cytotoxic and cytostatic effects, decreasing CDC20 expression in multiple NF1-mutant 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.
Insights
NF1-mutant melanomas lack targeted therapies. This study identified distinct genomic and transcriptomic profiles, revealing CDC20 as a therapeutic target when combined with MAPK pathway inhibitors.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Neurofibromatosis type 1 (NF1) mutations are found in a subset of melanomas.
- Currently, no targeted therapies exist for NF1-mutant melanomas, necessitating the identification of novel treatment strategies.
Purpose of the Study:
- To compare genomic and transcriptomic profiles of NF1-mutant and NF1 wild-type melanomas.
- To identify potential therapeutic targets for NF1-mutant melanoma.
- To evaluate the efficacy of novel combination regimens.
Main Methods:
- Genomic and transcriptomic analysis of melanoma samples.
- Quantitative PCR (qPCR) for alteration verification.
- The Cancer Genome Atlas (TCGA) data and immunohistochemistry for validation.
- Digital spatial profiling and multiplex immunofluorescence for signature validation.
- In vitro assays with low-passage cell lines to test combination therapies.
Main Results:
- NF1 mutations were identified in 27% of cases.
- NF1-mutant melanomas showed higher expression of proliferation markers MK167 and CDC20 compared to NF1 wild-type.
- LY6E was upregulated in tumor cells of NF1-mutant melanomas.
- Combination therapy of MAPK/ERK kinase inhibitors and CDC20 coinhibition demonstrated cytotoxic and cytostatic effects in vitro.
Conclusions:
- NF1-mutant melanoma exhibits a unique genomic and transcriptomic signature.
- CDC20 is a potential therapeutic target in NF1-mutant melanoma.
- Combining CDC20 inhibition with MAPK pathway inhibitors shows promise as a targeted regimen for this melanoma subtype.
