NTRK gene fusions cause the overexpression of TRK proteins1
NTRK genes (NTRK1, NTRK2, or NTRK3 ) tend to fuse with housekeeping genes. Housekeeping genes are necessary for both cell maintenance and existence, so they are expressed in all cell types throughout an organism. Examples of partner housekeeping genes that fuse with NTRK genes include: TPM3, TRIM24, and ETV6.2,11-149,10 Unless silenced, NTRK gene fusion leads to the expression of a chimeric protein, which retains the TRK kinase domain, but not the ligand-binding domain.1 These TRK fusion proteins are continuously turned on due to the genetic alteration. Therefore, NTRK gene fusions can lead to the development of solid tumors in a variety of tissue types.9,10
TRK fusion proteins are constitutively active1,2
- Fusions of NTRK genes have oncogenic potential regardless of fusion partner. Typically, dimerization of TRK proteins is mediated by the 5’ fusion partner, which allows the TRK portions of the proteins to autophosphorylate themselves independent of any regulation1,2
- As a result of this ligand-independent activation, TRK fusion proteins are constitutively active and propagate a constant signal cascade that causes cells to overproliferate and survive1,2
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