UMMS Affiliation

Department of Pediatrics; Division of Hematology/Oncology, Department of Pediatrics

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Document Type



Amino Acids, Peptides, and Proteins | Cancer Biology | Enzymes and Coenzymes | Neoplasms | Pediatrics


BACKGROUND: Neuroblastoma is a devastating disease accounting for 15% of all childhood cancer deaths. Yet, our understanding of key molecular drivers such as receptor tyrosine kinases (RTKs) in this pathology remains poorly clarified. Here, we provide a systematic analysis of the RTK superfamily in the context of neuroblastoma pathogenesis.

METHODS: Statistical correlations for all RTK family members' expression to neuroblastoma patient survival across 10 independent patient cohorts were annotated, synthesized, and ranked using the R2: Genomics Analysis and Visualization Platform. Gene expression of selected members across different cancer cell lines was further analyzed in the Cancer Cell Line Encyclopedia, part of the Cancer Dependency Map portal (depmap portal ( )). Finally, we provide a detailed literature review for highly ranked candidates.

RESULTS: Our analysis defined two subsets of RTKs showing robust associations with either better or worse survival, constituting potential novel players in neuroblastoma pathophysiology, diagnosis, and therapy. We review the available literature regarding the oncogenic functions of these RTKs, their roles in neuroblastoma pathophysiology, and potential utility as therapeutic targets.

CONCLUSIONS: Our systematic analysis and review of the RTK superfamily in neuroblastoma pathogenesis provides a new resource to guide the research community towards focused efforts investigating signaling pathways that contribute to neuroblastoma tumor establishment, growth, and/or aggressiveness and targeting these druggable molecules in novel therapeutic strategies.


DDR2, Kinase inhibitor, Neuroblastoma, RET, RTK

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Copyright © The Author(s) 2021. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit

DOI of Published Version



Rozen EJ, Shohet JM. Systematic review of the receptor tyrosine kinase superfamily in neuroblastoma pathophysiology. Cancer Metastasis Rev. 2022 Mar;41(1):33-52. doi: 10.1007/s10555-021-10001-7. Epub 2021 Oct 30. PMID: 34716856; PMCID: PMC8924100. Link to article on publisher's site

Journal/Book/Conference Title

Cancer metastasis reviews

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Creative Commons License

Creative Commons Attribution 4.0 License
This work is licensed under a Creative Commons Attribution 4.0 License.