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Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours

N Rajan1, R Elliott, O Clewes

  • 1Institute of Human Genetics, University of Newcastle upon Tyne, Newcastle upon Tyne, UK. neil.rajan@ncl.ac.uk

Oncogene
|May 10, 2011
PubMed

Insights

Loss of the CYLD gene increases cancer risk, particularly cylindromas. Targeting tropomyosin kinase (TRK) signaling, specifically TRKB and TRKC, shows promise for treating these CYLD-related tumors.

Area of Science:

  • Oncology
  • Genetics
  • Molecular Biology

Background:

  • Germline mutations in the CYLD tumor-suppressor gene predispose individuals to cutaneous appendageal tumors, notably cylindromas.
  • CYLD gene mutations are linked to a high risk of developing disfiguring tumors.

Purpose of the Study:

  • To investigate the genomic and transcriptomic alterations in CYLD-mutant tumors.
  • To identify potential therapeutic targets for CYLD-associated tumors.

Main Methods:

  • Array comparative genomic hybridization (aCGH) and gene expression microarray analysis were performed on CYLD mutant tumors.
  • Immunohistochemistry was used to assess TRK, ERK, and BCL2 expression.
  • RNA interference and small-molecule TRK inhibitor (lestaurtinib) were used in 3D cell cultures.

Main Results:

  • CYLD mutant tumors showed minimal copy-number aberrations, primarily loss of heterozygosity (LOH) at chromosome 16q.
  • Gene expression profiling revealed dysregulated tropomyosin kinase (TRK) signaling, with overexpression of TRKB and TRKC.
  • TRK inhibition reduced colony formation and proliferation in CYLD mutant tumor cell cultures.
  • TRKC overexpression was also found in sporadic basal cell carcinomas (BCCs).

Conclusions:

  • Dysregulated TRK signaling, particularly TRKB and TRKC overexpression, is a key feature of CYLD-mutant tumors.
  • TRK inhibition represents a potential therapeutic strategy for tumors with loss of functional CYLD, including some sporadic BCCs.

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