[3] NTRK3 codes for Tropomyosin receptor kinase C a NT-3 growth factor receptor cell surface protein that when bound to its growth factor ligand, neurotrophin-3, becomes an active tyrosine kinase that phosphorylates tyrosine residues on, and thereby stimulates, signaling proteins that promote the growth, survival, and proliferation of their parent cells.
The tyrosine kinase of the ETV6-NTRK3 fusion protein is dysfunctional in that it is continuously active in phosphorylating tyrosine residues on, and thereby continuously stimulating, proteins that promote the growth, survival, and proliferation of their parent cells.
[7][8][9][10][11][12][13] Because cancers associated with the expression of the ETV6-NTRK3 fusion protein are known or suspected of being a direct consequence of overly active ETV6-NTRK3's tyrosine kinase, it has been proposed that tyrosine kinase inhibitors with specificity for NTRK3 may be of therapeutic usefulness in these cancers.
Entrectinib is a pan-NTRK as well as an ALK and ROS1 tyrosine kinase inhibitor has been found useful in treating a single patient with ETV6-NRTK3 fusion gene-associated mammary analogue secretory carcinoma and has lend support to the clinical development of NTRK3-directed tyrosine kinase inhibitors to treat ETV6-NTRK3 fusion protein associated malignancies.
[10] Three clinical trials are in the recruitment phase for determining the efficacy of treating a wide range of solid tumors associated with mutated overactive tyrosine kinase proteins, including the ETV6-TRK3 protein, with larotrectinib, a non-selective inhibitor of NTRK1, NTRK2, and NTRK3 tyrosine kinases.