Roles of TrkC Signaling in the Regulation of Tumorigenicity and Metastasis of Cancer

Abstract

Tropomyosin receptor kinase (Trk) C contributes to the clinicopathology of a variety of human cancers, and new chimeric oncoproteins containing the tyrosine kinase domain of TrkC occur after fusion to the partner genes. Overexpression of TrkC and TrkC fusion proteins was observed in patients with a variety of cancers, including mesenchymal, hematopoietic, and those of epithelial cell lineage. Both microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) were involved in the regulation of TrkC expression through transcriptional and posttranscriptional alteration. Aberrant activation of TrkC and TrkC fusion proteins markedly induces the epithelial-mesenchymal transition (EMT) program, growth rate, tumorigenic capacity via constitutive activation of Ras-MAP kinase (MAPK), PI3K-AKT, and the JAK2-STAT3 pathway. The clinical trial of TrkC or TrkC fusion-positive cancers with newly developed Trk inhibitors demonstrated that Trk inhibitors were highly effective in inducing tumor regression in patients who do not harbor mutations in the kinase domain. Recently, there has been a progressive accumulation of mutations in TrkC or the TrkC fusion protein detected in the clinic and its related cancer cell lines caused by high-throughput DNA sequencing. Despite given the high overall response rate against Trk or Trk fusion proteins-positive solid tumors, acquired drug resistance was observed in patients with various cancers caused by mutations in the Trk kinase domain. To overcome acquired resistance caused by kinase domain mutation, next-generation Trk inhibitors have been developed, and these inhibitors are currently under investigation in clinical trials.

NTRK oncogenic fusions are exclusively associated with the serrated neoplasia pathway in the colorectum and begin to occur in sessile serrated lesions

“…47, 48 NTRK fusions are known to frequently have upstream partner genes with a coiled-coil domain, such as MPRIP, TPM3, TPR, TFG, ARHGEF2, LMNA, SQSTM1, TRIM63 , and PPL for NTRK1 fusions, TRIM24, PAN3 , and SQSTM1 for NTRK2 fusions, and TPM4, TFG, MYO5A, MYH9, STRN3, STRN , and EML4 for NTRK3 fusions. 47, 49…”

Identification of NTRK3 as a potential prognostic biomarker associated with tumor mutation burden and immune infiltration in bladder cancer

“…TRKC plays an important role in regulating angiogenesis, inducing tumor growth, preventing apoptosis and promoting metastasis. Abnormal activation of NTRK3 and its fusion proteins may regulate the epithelial-mesenchymal transition (EMT) process, tumor growth rate and tumorigenicity by activation of several signaling pathways [40].…”

Signalling Network of Breast Cancer Cells in Response to Progesterone

“…The tropomyosin receptor tyrosine kinases (TRKs) are primarily known for their roles in neuronal differentiation and survival. However, increasing evidence shows that TRK receptors can be found in a host of mammalian cell types to drive several cellular responses (Huang and Reichardt, 2003; Reichardt, 2006) Aberrations in TRK signalling, which can occur through events such as protein overexpression, alternative splicing, or gene amplification, can lead to disease such as cancer (Jin, 2020; Meng et al, 2019; Regua et al, 2019). The receptor tyrosine kinase NTRK2, activates GRB2-Ras-MAPK cascade in neurons and increases secretion by epithelial cells in culture in response to estrogen or progestin treatment and NTRK2 was identified as differentially expressed between stromal and epithelial breast cells which may have implications in invasion and metastasis (Wang et al, 2020) Merging of Fc-receptor and TRK signalling pathways (Fig.…”