History of NTRKs in Cancer Biology

A nervous system receptor tyrosine kinase (NTRK) was discovered in the colon.

Tropomyosin related kinases (Trk) were first discovered as fusion proteins with the actin binding protein tropomyosin. In 1986, decades before next generation sequencing techniques, Martin-Zanca and coworkers published a report of  a sequenced gene responsible for the malignant transformation of  a human colon carcinoma. They found gene sequences of both tropomyosin and a previously unknown protein tyrosine kinase. The predicted protein (641 amino acids) encoded by this oncogene seemed to have been formed by a somatic rearrangement that replaced the extracellular domain of a putative transmembrane receptor by the first 221 amino acids of a non-muscle tropomyosin molecule.   The tropomyosin fusion was located somewhere in the long arm of Chromosome 1 (now known as tropomyosin 3).  The actual location of non-muscle tropomyosin is 1q21.3 (Genecards). Locations of the fusion were 1q23-24 (Morris 1991), 1q32-41 (Miozzo 1990), and then 1q31 (Radice 1991).

Ardini and coworkers (2014) followed up on the work of Martin-Zanca (1986) by hypothesizing that the driving mutation of a colon carcinoma cell line KM12 (in use since 1988) was The TPM3-NTRK1 rearrangement.  With the retrospection of three decades and a sequenced human genome, these authors point out the closeness of the TPM3 and NTRK1 on the long arm of chromosome 1, 1q22-23 and 1q21-22, respectively.  The authors confirmed what happened to the extracellular domain (N-terminus) of NTRK1:  The break occurred in the protein coding region exon 8 of NTRK1 and in an intron between exon 7 and 8 of TPM3 (Ardini 2014).  The hollow arrow in Figure 1 points to the break point in the TPM3 gene.  As far as we know, the extracellular domain of TrkA fused to the C-terminus of tropomyosin 3 is not a functional protein.



Diagram showingTPM3 protein interacting with TrkA Kinase (NTRK1).

Figure 1. Conceptual view of TPM3-NTRK1 interaction.


The original TPM3-NTRK1 fusion will be discussed in greater detail as a blog in the post section of this website. In this section we will discuss in detail other cancer driving fusion proteins with the Trk family of kinases.

What we are learning

  1. The N-terminal fusion partners with the Trk kinases tend to be “housekeeping” proteins with broad to ubiquitous expression. A selectively expressed kinase that controls growth and differentiation is under the control of a house keeping gene promoter. We are exploring the implications of this scenario.
  2. Many of these fusion partner housekeeping proteins also form oligomers. Oligomers go far and beyond the simple ligand mediated dimerization one sees with activation of receptor tyrosine kinases.
  3. Some of these housekeeping, oligomer forming Trk fusion partners also serve as scaffolds for recruiting of downstream signal transduction proteins.  The downstream signal to the nucleus is to survive and divide.
  4. The ETV6-NTRK3 fusion mutation is becoming part of the definition for mammary analog secretory carcinoma (MASC).  We are in the process of connecting the cytology and immunocytochemistry to what this fusion protein is doing.

Important information

The history of Trk fusion kinases is rapidly unfolding.  Although these Trk fusion mutations are rare, they are very dangerous. The good news is that they can be treated with Trk inhibitors. Every new patient with a Trk fusion driven cancer successfully treated with a Trk inhibitor is an unfolding of this history.

There is an open NTRK fusion clinical trial that is actively enrolling any solid tumor patient with TRK fusions (STARTRK-2). For more information go to the NTRK trial website.