Skip to main content
SpringerLink
Log in

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

  • Research
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

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.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Data availability

No datasets were generated or analysed during the current study.

Abbreviations

FDA:

Food and Drug Administration

GEO:

Gene Expression Omnibus

IQR:

Interquartile range

NF1:

Neurofibromatosis type 1

PN:

Plexiform neurofibromas

Q1:

First quartile

Q3:

Third quartile, scRNAseq = single-cell RNA sequencing

References

  1. Hirbe AC, Gutmann DH (2014) Neurofibromatosis type 1: a multidisciplinary approach to care. Lancet Neurol 13:834–843

    Article  PubMed  Google Scholar 

  2. Sanchez LD, Bui A, Klesse LJ (2021) Targeted therapies for the neurofibromatoses. https://doi.org/10.3390/cancers13236032. Cancers 13.

  3. (2020) Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 383:1290

  4. Armstrong AE, Belzberg AJ, Crawford JR et al (2023) Treatment decisions and the use of MEK inhibitors for children with neurofibromatosis type 1-related plexiform neurofibromas. BMC Cancer 23:553

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Weiss BD, Wolters PL, Plotkin SR et al (2021) NF106: a neurofibromatosis clinical trials Consortium Phase II Trial of the MEK inhibitor Mirdametinib (PD-0325901) in adolescents and adults with NF1-Related plexiform neurofibromas. J Clin Oncol 39:797–806

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Tian J, Chen JH, Chao SX et al (2023) Combined PD-1, BRAF and MEK inhibition in BRAF colorectal cancer: a phase 2 trial. Nat Med 29:458–466

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Sharma P, Stecklein SR, Yoder R et al (2024) Clinical and biomarker findings of Neoadjuvant Pembrolizumab and Carboplatin Plus Docetaxel in Triple-negative breast Cancer: NeoPACT Phase 2 clinical trial. JAMA Oncol 10:227–235

    Article  PubMed  Google Scholar 

  8. Copley-Merriman C, Yang X, Juniper M et al (2021) Natural history and Disease Burden of Neurofibromatosis Type 1 with plexiform neurofibromas: a systematic literature review. Adolesc Health Med Ther 12:55–66

    PubMed  PubMed Central  Google Scholar 

  9. Hao Y, Hao S, Andersen-Nissen E et al (2021) Integrated analysis of multimodal single-cell data. Cell 184:3573–3587e29

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Wolbert J, Li X, Heming M et al (2020) Redefining the heterogeneity of peripheral nerve cells in health and autoimmunity. Proc Natl Acad Sci U S A 117:9466–9476

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Brosseau J-P, Sathe AA, Wang Y et al (2021) Human cutaneous neurofibroma matrisome revealed by single-cell RNA sequencing. Acta Neuropathol Commun 9:11

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Wu LMN, Zhang F, Rao R et al (2022) Single-cell multiomics identifies clinically relevant mesenchymal stem-like cells and key regulators for MPNST malignancy. Sci Adv 8:eabo5442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Ge L-L, Xing M-Y, Zhang H-B, Wang Z-C (2022) Neurofibroma Development in neurofibromatosis type 1: insights from Cellular Origin and Schwann Cell Lineage Development. https://doi.org/10.3390/cancers14184513. Cancers 14.

  14. Carroll SL, Ratner N (2008) How does the Schwann cell lineage form tumors in. NF1? Glia 56:1590–1605

    Article  PubMed  Google Scholar 

  15. Zhu Y, Ghosh P, Charnay P et al (2002) Neurofibromas in NF1: Schwann cell origin and role of tumor environment. Science 296:920–922

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Fustero-Torre C, Jiménez-Santos MJ, García-Martín S et al (2021) Beyondcell: targeting cancer therapeutic heterogeneity in single-cell RNA-seq data. Genome Med 13:187

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Subramanian A, Narayan R, Corsello SM et al (2017) A Next Generation Connectivity Map: L1000 platform and the first 1,000,000 profiles. Cell 171:1437–1452e17

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Barretina J, Caponigro G, Stransky N et al (2012) The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity. Nature 483:603–607

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Corsello SM, Nagari RT, Spangler RD et al (2020) Discovering the anti-cancer potential of non-oncology drugs by systematic viability profiling. Nat Cancer 1:235–248

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Wang W-N, Koguchi-Yoshioka H, Nimura K et al (2024) Distinct transcriptional profiles in the different phenotypes of Neurofibroma from the same subject with neurofibromatosis 1. J Invest Dermatol 144:133–141e4

    Article  CAS  PubMed  Google Scholar 

  21. Kershner LJ, Choi K, Wu J et al (2022) Multiple Nf1 Schwann cell populations reprogram the plexiform neurofibroma tumor microenvironment. JCI Insight 7. https://doi.org/10.1172/jci.insight.154513

  22. Roman Souza G, Abdalla A, Mahadevan D (2022) Clinical trials targeting neurofibromatoses-associated tumors: a systematic review. Neurooncol Adv 4:vdac005

    PubMed  PubMed Central  Google Scholar 

  23. Solares I, Viñal D, Morales-Conejo M et al (2021) Novel molecular targeted therapies for patients with neurofibromatosis type 1 with inoperable plexiform neurofibromas: a comprehensive review. ESMO Open 6:100223

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Gross AM, Wolters PL, Dombi E et al (2020) Selumetinib in Children with Inoperable Plexiform Neurofibromas. N Engl J Med 382:1430–1442

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Gross AM, Dombi E, Wolters PL et al (2023) Long-term safety and efficacy of selumetinib in children with neurofibromatosis type 1 on a phase 1/2 trial for inoperable plexiform neurofibromas. Neuro Oncol 25:1883–1894

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Chung DJ, Shah N, Wu J et al (2023) Randomized Phase II Trial of Dendritic Cell/Myeloma Fusion Vaccine with Lenalidomide Maintenance after upfront autologous hematopoietic cell transplantation for multiple myeloma: BMT CTN 1401. Clin Cancer Res 29:4784–4796

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Tian Z, You Y, Xiao M et al (2023) Inhibition of YAP sensitizes the Selumetinib treatment for neurofibromatosis type 1 related Plexiform Neurofibroma. Int J Med Sci 20:125–135

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Wang W, Cui X-W, Gu Y-H et al (2022) Combined cyclin-dependent kinase inhibition overcomes MAPK/Extracellular Signal-Regulated Kinase Kinase Inhibitor Resistance in Plexiform Neurofibroma of neurofibromatosis type I. J Invest Dermatol 142:613–623e7

    Article  CAS  PubMed  Google Scholar 

  29. Li S, Chen Z, Le LQ (2020) New insights into the neurofibroma tumor cells of origin. Neurooncol Adv 2:i13–i22

    PubMed  Google Scholar 

Download references

Acknowledgements

Not applicable.

Author information

Authors and Affiliations

  1. Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA

    Archis R. Bhandarkar & Robert J. Spinner

  2. Division of Pediatric Genetics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN, USA

    Dusica Babovic-Vuksanovic

  3. Division of Laboratory Genetics and Genomics, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Dusica Babovic-Vuksanovic

  4. Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, USA

    Aditya Raghunathan

  5. Department of Pediatric Hematology/Oncology, Section of Neuro-Oncology, Mayo Clinic, Rochester, MN, USA

    Jonathan Schwartz

  6. Johns Hopkins School of Medicine, Johns Hopkins University, Baltimore, MD, USA

    Shaan Bhandarkar

Authors
  1. Archis R. Bhandarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaan Bhandarkar
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dusica Babovic-Vuksanovic
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Aditya Raghunathan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Jonathan Schwartz
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Robert J. Spinner
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

ARB: conceptualization, methodology, writing - original draft, writing- reviewing and editing; SB: conceptualization, methodology, analysis, writing - original draft, writing- reviewing and editing; DB: writing- reviewing and editing; AR: writing- reviewing and editing; JS: writing- reviewing and editing; RJS: conceptualization, writing- reviewing and editing, supervision.

Corresponding author

Correspondence to Robert J. Spinner.

Ethics declarations

Competing interests

The authors declare no competing interests.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Below is the link to the electronic supplementary material.

Supplementary Material 1

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Bhandarkar, A.R., Bhandarkar, S., Babovic-Vuksanovic, D. et al. Precision oncology in neurofibromatosis type 1: quantification of differential sensitivity to selumetinib in plexiform neurofibromas using single-cell RNA sequencing. J Neurooncol (2024). https://doi.org/10.1007/s11060-024-04711-5

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s11060-024-04711-5

Keywords

Search

Navigation