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Assessment of Resistance to Tyrosine Kinase Inhibitors by an Interrogation of Signal Transduction Pathways by Antibody Arrays
Published on: September 19, 2018
Kinome profiling reveals pathogenic variant specific protein signalling networks in MEN2 children with Medullary
B Rix1,2, R Chauhan2, Z Masoumi1
1ProteoStem Lab, Centre for Blood Research, York Biomedical Research Institute, Department of Biology, University of York, York, UK.
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 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.
Insights
This study investigated the functional kinome in Multiple Endocrine Neoplasia Type 2 (MEN2) patients. Findings reveal subtype-specific signaling pathway alterations, identifying potential new therapeutic targets for MEN2.
Area of Science:
- Oncology
- Genetics
- Molecular Biology
Background:
- Multiple Endocrine Neoplasia Type 2 (MEN2) is an inherited disorder caused by RET gene mutations.
- Tumor development in MEN2 is unpredictable, highlighting the need for deeper molecular understanding.
- Current treatments lack curative options, emphasizing the need for novel therapeutic targets.
Purpose of the Study:
- To investigate the functional kinome in familial MEN2 patients.
- To identify MEN2 subtype and RET pathogenic variant-specific molecular alterations.
- To uncover novel therapeutic targets for MEN2.
Main Methods:
- Functional kinome profiling of 24 familial MEN2 patients.
- Analysis of signaling pathways including mTOR, PKA, and NF-κB.
- Validation of identified alterations in patient thyroid tissue.
Main Results:
- Identified specific alterations in signaling pathways (mTOR, PKA, NF-κB, focal adhesions) linked to MEN2 subtypes and RET variants.
- Demonstrated subtype and variant-specific molecular drivers of MEN2.
- Validated these findings in patient thyroid tissues.
Conclusions:
- The study uncovers novel, specific molecular drivers for MEN2 and its subtypes.
- Identified potential new therapeutic targets for MEN2, advancing precision medicine.
- Provides a foundation for developing targeted therapies beyond prophylactic thyroidectomy.
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