Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer
Multiple Endocrine Neoplasia Type 2 (MEN2) is an autosomal dominant disease caused by pathogenic variants in the receptor tyrosine kinase RET, with strong genotype-phenotype correlations. The development and progression of these tumours are not always predictable even within families with the same RET pathogenic variant, demonstrating a need for better understanding of the underlying molecular mechanisms. Precision molecular medicine is not widely used and the standard of care remains prophylactic thyroidectomy. This absence of curative approaches is exacerbated by the lack of novel therapeutic markers/targets. In this study, we investigated the functional kinome of 24 familial MEN2 patients. We identified MEN2 subtype and RET pathogenic variant-specific alterations in signalling pathways including mTOR, PKA, NF-κB and focal adhesions, which were validated in patient thyroid tissue. Overall, our study of MEN2 functional kinomes uncovers novel specific drivers of MEN2 disease and its pathogenic variant subtypes, identifying new potential therapeutic targets for MEN2.
Authors
- Caroline Brain (ORCID: https://orcid.org/0000-0002-0630-6532)
- Neil Q. McDonald (ORCID: https://orcid.org/0000-0003-0975-6325)
- Dominique A. Bonnet (ORCID: https://orcid.org/0000-0002-4735-5226)
- Charles Swanton (ORCID: https://orcid.org/0000-0002-4299-3018)
- Louise Izatt (ORCID: https://orcid.org/0000-0003-1258-4843)
- Eva Grönroos (ORCID: https://orcid.org/0000-0001-8303-5409)
- Seyedeh Zahra Masoumi (ORCID: https://orcid.org/0000-0002-2045-3707)
- Olumide Ogunbiyi (ORCID: https://orcid.org/0000-0001-5208-5526)
- Tom Kurzawinski
- William Grey (ORCID: https://orcid.org/0000-0001-8209-5645)
- Beatrice Rix
- Katherine Swarbrick
- Rakhee Chauhan
Institutions
- New York Blood Center (US)
- King's College London (GB)
- Guy's and St Thomas' NHS Foundation Trust (GB)
- Great Ormond Street Hospital (GB)
- The Francis Crick Institute (GB)
- University College London (GB)
- University of York (GB)
Publication Details
- Journal
- npj Precision Oncology
- Published
- 2025-05-02
- DOI
- https://doi.org/10.1038/s41698-025-00919-4
- Citations
- 1
- Primary Topic
- Thyroid Cancer Diagnosis and Treatment
- Type
- article
- Field-Weighted Citation Impact
- 1.29
Funders
- Breast Cancer Research Foundation
- European Hematology Association
- Indian National Science Academy
- Wellcome Trust
- Francis Crick Institute
- Children's Cancer and Leukaemia Group
- UK Research and Innovation
- Mark Foundation For Cancer Research
- Leukaemia UK
- Cancer Research UK
- National Institute for Health and Care Research
- Royal Society
- University College London
- European Commission
- Rosetrees Trust
- Little Princess Trust
- Medical Research Council
- European Research Council
- Great Ormond Street Institute of Child Health