NTRK3

NTRK is a nerve growth factor receptor, belonging to tyrosine kinases, the family of NTRK includes three highly homologous TRK proteins TRKA, TRKB and TRKC, encoded by NTRK1, NTRK2 and NTRK3 genes respectively. NTRK plays an important role in the development of the central nervous system, and the three homologous proteins bind to different nerve growth factor ligands. When NTRK protein binds to the corresponding ligand, phosphorylation occurs, which activates a variety of downstream signaling pathways, such as MAPK, PI3K-Akt, and PLCγ, thus regulating cell proliferation, cell differentiation, cell metabolism, apoptosis and other biological processes. Chromosomal variation may lead to the fusion of NTRK with other genes, thus forming a fusion tumor driver gene, which can lead to the enhancement of TRK protein kinase activity, over-activation of downstream signaling pathways, and promotion of tumor cell growth and proliferation, which may lead to the occurrence of cancer (PMID: 16699811). The incidence of fusion of NTRK in all tumors is low, about 1-3% on average, but it can occur in a variety of tumors, and the incidence varies greatly in each tumor. Among common malignant tumors, such as lung cancer, colorectal cancer, head and neck cancer, the incidence is less than 3%, while in some rare tumor types, For example, the incidence of secretory breast cancer and infantile fibrosarcoma can be as high as over 90% (PMID: 30637364).

Currently, most NTRK targeted drugs belong to kinase inhibitors, which inhibit the catalytic activity of kinase by competing with ATP for binding sites. Among the first-generation TRK inhibitors already approved by the FDA, larotrectinib and entretinib were approved in November 2018 and June 2019, respectively, Both drugs are indicated for the treatment of solid tumors in adults and children with NTRK gene fusion, metastatic disease without known resistant mutations, postoperative disease progression, or no alternative therapy. Both drugs belong to the broad spectrum of anticancer agents of all cancers (PMID: 30333516). Entretinib was also approved for the treatment of patients with ROS1 positive advanced non-small cell lung cancer. Now several second-generation inhibitors targeting drug-resistant mutations in NTRK fusion genes have entered the clinical stage (PMID: 31979374, PMID: 30333516). For example, the targeted drug PLX7486, which is not limited to specific cancer, is used in solid tumors with NTRK gene fusion or activation mutation (NCT01804530), and LOXO-195 (Selitrectinib) is used in children and adult solid tumors with drug-resistant mutation in NTRK fusion gene (NCT03206931) and TPX-0 05 (Repotrectinib) for children and adults with locally advanced or metastatic NTRK, ROS1, or ALK gene fusions (NCT04094610). There are also several drugs for NTRK gene fusion in single cancer, such as NTRK gene fusion inhibitors PLX7486 and Milciclib for pancreatic cancer and thymic cancer respectively.