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.

Keywords: TrkC; TrkC fusion; TrkC inhibitor; somatic mutation; targeted therapies.

Figure 1

Somatic mutation frequency of TrkC in patients of 36 various cancer types. (A) Total of 530 mutations in TrkC, including 454 missense mutations, 70 truncating mutations, three inframe mutations, and discovered in patients of various cancers. Specifically, 177 of 530 mutations identified in the tyrosine kinase domain of TrkC. LRRNT: Leucine-rich repeat N-terminal domain, LRR1; Leucine-rich repeat region 1, LRR2: Leucine-rich repeat region 1, LRRCT: Leucine-rich repeat C-terminal domain, Ig-like C2: Immunoglobulin-C2-set domain, TM: transmembrane domain. (B) The overall frequency of mutated TrkC in cancer types. cSCC [50], DM [51], CM: TCGA Dataset, BCC: [52], LA: [53], EC: TCGA Dataset, VV-SCC: [54], NSCLC: [55], UTUC [56], CTCL: [57], AS: TCGA Dataset, CRC: [58], GC: TCGA Dataset, CSCC: TCGA Dataset, EAC: [59], HNC: TCGA Dataset, RMS: [60], PAC: [61], DLBCL: TCGA Dataset, HCC: TCGA Dataset, AC: Ampullary carcinoma [62], UCS: TCGA Dataset, BUC: TCGA Dataset, RCC: TCGA Dataset, PA: [63], CC: [64], GC: [65], PDTC & ATC: [66,67], OSC: TCGA Dataset, BC: [68], CCRCC: TCGA Dataset, CLL: [69], DG: [70].

Figure 3

Diagram of TrkC biology and signaling identified in various cancers. TrkC and TrkC isoform can enhance and activate downstream of TRK signaling, including PLCγ/IP3/DAG [1,148,149], RAS/MAPK [1,79,132,148], PI3K/AKT [1,79,132,148], and JAK/STAT signaling [20,135], resulting in the promotion of survival, aggressiveness, chemoresistance, and generation of CSCs of cancer.

Figure 2

Diagram of TrkC fusion proteins identified in various cancers. In most TrkC fusion proteins, the carboxy-terminal of the TrkC protein, including the tyrosine kinase domain, fused with inframe to the amino-terminal binding partner. Nucleotide sequences indicate the breakpoint. CC: Coiled-coil, CC: Coiled-coil, HLH: Helix loop Helix, LRRCT: Leucine-rich repeat C-terminal domain, LRRNT: Leucine-rich repeat N-terminal domain, RRM: RNA recognition motif, BTB: protein-protein interaction, BACK: BTB and C-terminal Kelch, PB1: Phox and Bem1p, SH2: Src Homology 2, SH3: Src Homology 3, MYSc: Myosin motor, UBCs: Ubiquitin-conjugating enzyme E2, WH1: WASP homology region 1, ZnF: Zinc-binding, and TM: Transmembrane.