Precision oncology in neurofibromatosis type 1: quantification of differential sensitivity to selumetinib in plexiform neurofibromas using single-cell RNA sequencing.
J Neurooncol
; 169(1): 147-153, 2024 Aug.
Article
em En
| MEDLINE
| ID: mdl-38739187
ABSTRACT
PURPOSE:
Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level.METHODS:
scRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library.RESULTS:
A total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR 1,029 cells, Q1-Q3 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR 0.14, Q1-Q3 0.59-0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR 0.21, Q1-Q3 0.27-0.48, n = 1,034 cells).CONCLUSIONS:
scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials.Palavras-chave
Texto completo:
1
Base de dados:
MEDLINE
Assunto principal:
Benzimidazóis
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Neurofibromatose 1
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Neurofibroma Plexiforme
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Análise de Célula Única
Limite:
Adolescent
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Adult
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Child
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Female
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Humans
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Male
Idioma:
En
Revista:
J Neurooncol
Ano de publicação:
2024
Tipo de documento:
Article
País de afiliação:
Estados Unidos