Precision oncology in neurofibromatosis type 1: quantification of differential sensitivity to selumetinib in plexiform neurofibromas using single-cell RNA sequencing

Archis R Bhandarkar; Shaan Bhandarkar; Dusica Babovic-Vuksanovic; Aditya Raghunathan; Jonathan Schwartz; Robert J Spinner

doi:10.1007/s11060-024-04711-5

Precision oncology in neurofibromatosis type 1: quantification of differential sensitivity to selumetinib in plexiform neurofibromas using single-cell RNA sequencing

J Neurooncol. 2024 May 13. doi: 10.1007/s11060-024-04711-5. Online ahead of print.

Authors

Archis R Bhandarkar¹, Shaan Bhandarkar², Dusica Babovic-Vuksanovic^{3

4}, Aditya Raghunathan⁵, Jonathan Schwartz⁶, Robert J Spinner⁷

Affiliations

¹ Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA.
² Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA.
³ Division of Pediatric Genetics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA.
⁴ Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁵ Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA.
⁶ Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN, USA.
⁷ Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA. Spinner.Robert@mayo.edu.

PMID: 38739187
DOI: 10.1007/s11060-024-04711-5

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.

Keywords: Neurofibroma; Neurofibromatosis; Precision oncology; RNA sequencing; Selumetinib; Targeted therapy.