Targeting Tropomyosin Receptor Kinase in Cutaneous CYLD Defective Tumors With Pegcantratinib

Abstract

Key Points Question Can targeting tropomyosin receptor kinase with an existing topical kinase inhibitor, pegcantratinib, 0.5% (wt/wt), reduce cutaneous cylindroma tumor volume more than placebo? Findings In this phase 2 clinical trial that included 150 tumors from 15 patients with CYLD cutaneous syndrome, pegcantratinib-treated tumors did not achieve the primary outcome of response. Molecular analyses of biopsy material demonstrated drug penetration; however, drug concentrations achieved were inadequate to abrogate tropomyosin receptor kinase signaling in CYLD cutaneous syndrome tumors. Meaning These findings indicate that further studies should examine dose-escalation of pegcantratinib in these patients.

Epigenetic dysregulation underpins tumorigenesis in a cutaneous tumor syndrome

“…To assess the impact of DNMT3A mutations on methylation patterns, eight samples genotyped by TDS were studied using genome-wide DNA methylation arrays. Unsupervised clustering of the 250 most variably methylated loci revealed a distinct cluster comprising five 5 tumors with predicted DNMT3A2 isoform specific mutations ("DNMT3A2-mutated") ( Fig. 3b).…”

“…We comprehensively profiled the genomic landscape of 42 benign and malignant tumors across 13 individuals from four multigenerational families. 5 Novel driver mutations were found in epigenetic modifiers DNMT3A and BCOR in 29% of benign tumors. Multi-level and microdissected sampling strikingly reveal that many clones with different DNMT3A mutations exist in these benign tumors, suggesting that intra-tumor heterogeneity is common.…”

“…1a-b) offer an opportunity to address this knowledge gap and novel molecular insights into cancer can be gained. They may reveal unexpected driver mutations 4 , highlight mechanisms that may be targetable with repurposed drugs developed for other cancers 5 , or refine models of tumor growth and 5 patterning. CCS patients develop multiple skin tumors named cylindroma, spiradenoma and trichoepithelioma, a histophenotypic spectrum of hair follicle-related tumors consistent with the hypothesis that they arise in hair follicle stem cells 6,7 .…”

“…Corroborating this, murine CYLD knockout models develop skin papillomas following chemical carcinogenesis that demonstrate increased expression of NF-kB target genes such as cyclin D1 mediated by dysregulation of BCL3 19 . Furthermore, CYLD has been shown to negatively regulate various oncogenic signalling pathways that are also relevant in hair development in embryogenesis, 5 including Wnt 20 , Notch and TGF-b 6 .…”

“…1b) 15 . Tumors demonstrated neither recurrent structural rearrangements nor recurrent copy number aberrations 5 ( Supplementary Fig. 2).…”