Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer

Rix, B. and Chauhan, R. and Masoumi, Z. and Grönroos, E. and Brain, C. and Ogunbiyi, O.K. and Swarbrick, K. and Swanton, C. and Bonnet, D. and Kurzawinski, T.R. and Izatt, L. and McDonald, Neil Q. and Grey, W. (2025) Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary Thyroid Cancer. Precision Oncology 9 (125), ISSN 2397-768X.

Abstract

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 variants, demonstrating a need for better understanding of the underlying molecular mechanisms. Precision molecular medicine approaches are not widely used and the standard of care remains prophylactic thyroidectomy. This lack of 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, validating these findings 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.

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