Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours

N Rajan, R Elliott, O Clewes, A Mackay, J S Reis-Filho, J Burn, J Langtry, M Sieber-Blum, C J Lord, A Ashworth

Research output: Contribution to journalArticlepeer-review

Abstract

Individuals with germline mutations in the tumour-suppressor gene CYLD are at high risk of developing disfiguring cutaneous appendageal tumours, the defining tumour being the highly organised cylindroma. Here, we analysed CYLD mutant tumour genomes by array comparative genomic hybridisation and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy-number aberrations apart from LOH chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours showed dysregulated tropomyosin kinase (TRK) signalling, with overexpression of TRKB and TRKC in tumours when compared with perilesional skin. Immunohistochemical analysis of a tumour microarray showed strong membranous TRKB and TRKC staining in cylindromas, as well as elevated levels of ERK phosphorylation and BCL2 expression. Membranous TRKC overexpression was also observed in 70% of sporadic BCCs. RNA interference-mediated silencing of TRKB and TRKC, as well as treatment with the small-molecule TRK inhibitor lestaurtinib, reduced colony formation and proliferation in 3D primary cell cultures established from CYLD mutant tumours. These results suggest that TRK inhibition could be used as a strategy to treat tumours with loss of functional CYLD.

Original languageEnglish
Pages (from-to)4243-60
Number of pages18
JournalOncogene
Volume30
Issue number41
DOIs
Publication statusPublished - 13 Oct 2011

Keywords

  • Adenoma, Sweat Gland/genetics
  • Carbazoles/pharmacology
  • Carcinoma, Adenoid Cystic/genetics
  • Cluster Analysis
  • Comparative Genomic Hybridization
  • Deubiquitinating Enzyme CYLD
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Immunoblotting
  • Immunohistochemistry
  • Mutation
  • Neoplasms/genetics
  • Neoplasms, Basal Cell/genetics
  • Oligonucleotide Array Sequence Analysis
  • Primary Cell Culture
  • Protein Kinases/genetics
  • RNA Interference
  • Receptor, trkB/antagonists & inhibitors
  • Receptor, trkC/antagonists & inhibitors
  • Reverse Transcriptase Polymerase Chain Reaction
  • Signal Transduction/genetics
  • Sweat Gland Neoplasms/genetics
  • Tissue Array Analysis
  • Tumor Cells, Cultured
  • Tumor Suppressor Proteins/genetics

Fingerprint Dive into the research topics of 'Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours'. Together they form a unique fingerprint.

Cite this