A brief history of NTRK fusions

NTRK fusions (Tropomyosin related kinase fusion proteins) were discovered thirty years ago in search for colon carcinoma associated oncogenes (Martin-Zanca 1986). In those days, fusion proteins were called chimeras, after a Greek mythological monster.  The syntax in most common usage today is “fusion protein”, produced by a “gene rearrangement”.

In the following images NTRK (gene) kinase domains are colored purple while domains from partner fusion proteins are colored cyan and much more.  Some gene fusions “drive” cancers while others are just “passenger” mutations.

picture showing chimeras of a cow with a tiger head and cow with a penguin head

Figure 1. Whimsical examples of chimeras

Some chimeras and fusion proteins may be more dangerous than others.

Diagram showing NTRK fusions compared to wild type NTRK and their relation to various cancer types

Figure 2. NTRK1 gene fusions that drive cancer (courtesy of Ignyta and their NTRK information)

In our posts we have expanded on how the TPM3-NTRK1, LMNA-NTRK1, NFASC-NTRK1, and SQSTM-NTRK1 gene fusions can be translated into some cancer driving proteins.

Diagram showing NTRK2 fusions compared to wild type NTRK and their relation to various cancer types

Figure 3. NTRK2 gene fusions that drive cancer.

In our posts we are reviewing interesting aspects of the QK1-NTRK2 and NACC2-NTRK2 gene fusions and how their protein gene products may cause uncontrolled cell growth.

Diagram showing NTRK3 fusions compared to wild type NTRK and their relation to various cancer types

Figure 4. NTRK3 gene fusions that drive cancer.

The ETV6-NTRK3 gene fusion has a particularly interesting protein product, TEL-TrkC, that is discussed in one of our posts.

We will not be discussing how gene fusions occur.  Two of many excellent reviews are  Kumar-Sinha 2015 and  Latysheva 2016.

In our posts we are reviewing an inexpensive and streamlined approach to identifying cancer driving fusions of kinase domains the Trk family, ALK, and ROS1 (Murphy 2016).   This is an elegant assay that ignores passenger fusions and the occasional fusion that occurs at the level of messenger RNA.

While we are not at the level of fine tuning use of targeted cancer driving kinase inhibitors based on the fusion partners, the detection method of Murphy 2016 will aid in that possibility.

Important information

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

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