TRKing down an old oncogene in a new era of targeted therapy

Abstract

The use of high-throughput next-generation sequencing techniques in multiple tumor types during the last few years has identified NTRK1, 2, and 3 gene rearrangements encoding novel oncogenic fusions in 19 different tumor types to date. These recent developments have led us to revisit an old oncogene, Trk (originally identified as OncD), which encodes the TPM3-NTRK1 gene fusion and was one of the first transforming chromosomal rearrangements identified 32 years ago. However, no drug has yet been approved by the FDA for cancers harboring this oncogene. This review will discuss the biology of the TRK family of receptors, their role in human cancer, the types of oncogenic alterations, and drugs that are currently in development for this family of oncogene targets.

Significance: Precision oncology approaches have accelerated recently due to advancements in our ability to detect oncogenic mutations in tumor samples. Oncogenic alterations, most commonly gene fusions, have now been detected for the genes encoding the TRKA, TRKB, and TRKC receptor tyrosine kinases across multiple tumor types. The scientific rationale for the targeting of the TRK oncogene family will be discussed here.

Figure 1. Trk fusion signaling

Schematic showing common signaling mechanisms for an example of a cytoplasmic (non-membrane bound) chimeric Trk gene fusion are shown. Gene fusions are constitutively activated, or phosphorylated, often as a result of dimerization mediated by sequences in the 5′ gene. SH2 and PTB domain containing adaptors compete for binding at specific tyrosine residues, which most frequently results in propagation of the downstream signaling pathways shown.

Figure 2. TrkA oncogenic variants and Trk gene fusion partners

A. Schematic of TrkA isoforms, deletions, and mutations are shown. Mutations are shown in the TrkAI isoform. Amino acid position numbers are shown in black. B. Schematic showing the known NTRK1 (blue), NTRK2 (red), and NTRK3 (green) fusions and the tumor types in which they have been identified. It is important to note that not all of these gene fusions have yet been characterized functionally, but each one occurred in-frame with an intact Trk kinase domain and are thus potentially oncogenic. Known 5′ dimerization domains are shown in grey, and 3′ domains shown in blue (NTRK1), red (NTRK2), or green (NTRK3). No protein domains are shown for fusions that lack a reported breakpoint. Fusion proteins are not drawn to scale.