Dysregulated TRK signalling is a therapeutic target in CYLD defective tumours

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 (aCGH) and gene expression microarray analysis. CYLD mutant tumours were characterised by an absence of copy number aberrations apart from loss-of-heterozygosity at chromosome 16q, the genomic location of the CYLD gene. Gene expression profiling of CYLD mutant tumours revealed dysregulated tropomyosin kinase (TRK) signalling with overexpression of TRKB and TRKC in tumours when compared to perilesional skin. Immunohistochemical analysis of a tumour microarray demonstrated 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 basal cell carcinomas. 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 three-dimensional 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.