Tropomyosin Receptor Kinase A Expression on Merkel Cell Carcinoma Cells

Wehkamp, Ulrike; Stern, Sophie; Krüger, Sandra; Hauschild, Axel; Röcken, Christoph; Egberts, Friederike

doi:10.1001/jamadermatol.2017.2495

Cited by 7 publications

(4 citation statements)

References 16 publications

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“…Predominant TrkAIII mRNA expression in advanced stage and recurrent MCPyV positive MCCs, with evidence of intracellular TrkAIII expression and activation, also extends previous reports of a potential oncogenic role for TrkA in MCC [14, 15] but would negate a proposed requirement for NGF-expressing MCC-infiltrating inflammatory cells for activation [15], which may be more relevant to MCPyV negative MCCs, BCCs and SCCs that express fully spliced TrkA receptors (this study, [37, 38]). In addition, confocal IF in an advanced stage MCPyV positive MCC exhibiting exclusive TrkAIII mRNA expression also detected anti-TrkA immunoreactivity co-localised with γ-tubulin, suggesting that TrkAIII may localise to the centrosome in MCCs.…”

Section: Discussionsupporting

confidence: 85%

“…Recently, detection of extensive neurotrophin receptor tropomyosin-related tyrosine kinase A receptor (TrkA) immunoreactivity in MCC tissues has prompted suggestions of an oncogenic role for TrkA in this tumour-type [14, 15]. TrkA oncogenes are activated and play significant roles in many human cancers, and cancers driven by TrkA oncogenes exhibit profound, long-lived responses to novel clinically approved Trk inhibitors, such as Larotrectinib [16–18], suggesting that TrkA-targeted therapy may have a place in the treatment of MCC.…”

Section: Introductionmentioning

confidence: 99%

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A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

Cappabianca

Guadagni

Maccarone

et al. 2019

J Exp Clin Cancer Res

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BackgroundMerkel cell carcinomas (MCCs) are rare, aggressive, therapeutically-challenging skin tumours that are increasing in incidence and have poor survival rates. The majority are caused by genomic Merkel cell polyomavirus (MCPyV) integration and MCPyV T-antigen expression. Recently, a potential oncogenic role for the tropomyosin-related tyrosine kinase A receptor (TrkA) has been proposed in MCC. Alternative TrkAIII splicing is a TrkA oncogenic activation mechanism that can be promoted by SV40 large T-antigen, an analogue of MCPyV large T-antigen. In this pilot study, therefore, we have evaluated TrkAIII splicing as a novel potential oncogenic mechanism and therapeutic target in MCPyV positive MCC.MethodsFormalin-fixed paraffin-embedded MCC tissues, consisting of 10 stage IV, 1 stage IIIB, 1 stage IIB, 4 stage IIA and 2 stage I tumours, from patients diagnosed and treated from September 2006 to March, 2019, at the University of L’Aquila, L’Aquila, Italy, were compared to 3 primary basal cell carcinomas (BCCs), 3 primary squamous cell carcinomas (SCCs) and 2 normal skin samples by RT-PCR for MCPyV large T-antigen, small T-antigen, VP-1 expression and alternative TrkAIII splicing and by indirect IF for evidence of intracellular TrkA isoform expression and activation.Results9 of 10 Recurrent stage IV MCCs were from patients (P.1–3) treated with surgery plus loco-regional Melphalan chemotherapy and remaining MMCs, including 1 stage IV tumour, were from patients treated with surgery alone (P. 4–11). All MCPyV positive MCCs exhibiting MCPyV large T-antigen expression (17 of 18MCCs, 90%) exhibited alternative TrkAIII mRNA splicing (100%), which was exclusive in a significant number and predominant (> 50%) in all stage IV MCCs and the majority of stage 1-III MCCs. MCCs with higher TrkAIII to 18S rRNA expression ratios also exhibited strong or intermediate immunoreactivity to anti-TrkA antibodies, consistent with cytoplasmic TrkAIII expression and activation. In contrast, the MCPyV negative MCC, BCCs, SCCs and normal skin tissues all exhibited exclusive fully-spliced TrkA mRNA expression, associated with variable immunoreactivity for non-phosphorylated but not phosphorylated TrkA.ConclusionsMCPyV positive MCCs but not MCPyV negative MCC, BCCs and SCCs exhibit predominant alternative TrkAIII splicing, with evidence of intracellular TrkAIII activation. This establishes a new potential MCC subset, unveils a novel potential MCPyV oncogenic mechanism and identifies TrkAIII as a novel potential therapeutic target in MCPyV positive MCC.

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Section: Discussionsupporting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

Cappabianca

Guadagni

Maccarone

et al. 2019

J Exp Clin Cancer Res

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“…TrkA expression may be characteristic of MCC: In one MCC case series, all 36 specimens exhibited cytoplasmic TrkA, although staining was generally weak (only 2 (6%) samples stained strongly for TrkA). [ 21 ] Its ligand, nerve growth factor (NGF) is expressed by tumor-associated interdigitating cells in roughly 70% of MCC cases – a sensical observation for a tumor of neuroendocrine origin [ 22 ]. A small study ( n = 10) revealed that MCCP tumors may tend to display activating alternative splicing of NTRK1 mRNA.…”

Section: Discussionmentioning

confidence: 99%

Predictors of immunotherapy benefit in Merkel cell carcinoma

et al. 2020

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Merkel cell carcinoma is a rare cancer for which immune checkpoint blockade is standard-of-care for recurrent/metastatic disease. However, not all patients benefit from immunotherapy. A greater understanding of molecular mechanisms and predictive biomarkers are unmet needs. We retrospectively analyzed electronic health records and next-generation sequencing data of 45 patients treated at our institution from 2013 to 2020 to understand clinical and genomic correlates of benefit from immunotherapy. Our cohort predominantly included individuals with stage III disease at primary disease diagnosis and individuals with stage IV disease at recurrent/metastatic disease diagnosis. Most received immunotherapy as firstline treatment. 43% experienced objective response (median duration of response 24.2 months, 95% confidence interval 8.8-not reached). Median overall survival was 15.5 months (95% confidence interval 9.0-28.7) (median follow-up 25.2 months). Less advanced stage at primary disease diagnosis and shorter disease-free interval between completion of initial treatment and recurrence were each associated with greater odds of response (odds ratio of 0.06, p = 0.04 for stage; odds ratio 0.75, p = 0.05 for disease-free interval). Single-nucleotide variants in ARID2 and NTRK1 were associated with response (p = 0.05, without Bonferroni correction), while none of Merkel cell polyomavirus status, total mutational burden, ultraviolet mutational signatures, and copy-number alterations predicted outcomes. Patients with shorter disease-free interval may be particularly suitable immunotherapy candidates. Our molecular findings point to ARID2 and NTRK1 as potential predictive markers and/ or therapeutic targets (e.g., with Trk inhibitors), although this association needs to be confirmed in a larger sample.

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“…Whether Trk overexpression or overactivation caused by chromosomal rearrangements and NTRK gene fusions (Amatu et al 2016) is also existent in NET should be investigated in further studies. Interestingly, in the malignant neuroendocrine Merkel cell carcinoma, expression of TrkA was found in all tested tumor specimens (36/36), underlining a possible therapeutic relevance of Trk blockage in NETs not only from the GEP system (Wehkamp et al 2017).…”

Section: Endocrine-related Cancermentioning

confidence: 92%

Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors

Prada

Heinzle

Knösel

et al. 2018

Endocrine-Related Cancer

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Tropomyosin receptor kinase (Trk) inhibitors are investigated as a novel targeted therapy in various cancers. We investigated the effects of the pan-Trk inhibitor GNF-5837 in human neuroendocrine tumor (NET) cells. The human neuroendocrine pancreatic BON1, bronchopulmonary NCI-H727 and ileal GOT1 cell lines were treated with GNF-5837 alone and in combination with everolimus. Cell viability decreased in a time- and dose-dependent manner in GOT1 cells in response to GNF-5837 treatment, while treatment in BON1 and NCI-H727 cells showed no effect on cellular viability. Trk receptor expression determined GNF-5837 sensitivity. GNF-5837 caused downregulation of PI3K-Akt-mTOR signaling, Ras-Raf-MEK-ERK signaling, the cell cycle and increased apoptotic cell death. The combinational treatment of GNF-5837 with everolimus showed a significant enhancement in inhibition of cell viability vs single substance treatments, due to a cooperative PI3K-Akt-mTOR and Ras-Raf-MEK-ERK pathway downregulation, as well as an enhanced cell cycle component downregulation. Immunohistochemical staining for Trk receptors were performed using a tissue microarray containing 107 tumor samples of gastroenteropancreatic NETs. Immunohistochemical staining with TrkA receptor and pan-Trk receptor antibodies revealed a positive staining in pancreatic NETs in 24.2% (8/33) and 33.3% (11/33), respectively. We demonstrated that the pan-Trk inhibitor GNF-5837 has promising anti-tumoral properties in human NET cell lines expressing the TrkA receptor. Immunohistochemical or molecular screening for Trk expression particularly in pancreatic NETs might serve as predictive marker for molecular targeted therapy with Trk inhibitors.

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Tropomyosin Receptor Kinase A Expression on Merkel Cell Carcinoma Cells

Cited by 7 publications

References 16 publications

A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

A pilot study of alternative TrkAIII splicing in Merkel cell carcinoma: a potential oncogenic mechanism and novel therapeutic target

Predictors of immunotherapy benefit in Merkel cell carcinoma

Tropomyosin receptor kinase: a novel target in screened neuroendocrine tumors

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