In the last three years, two TRK inhibitors, larotrectinib and entrectinib, gained the approval for NTRK fusion-positive cancer patients, regardless of tumour histology, by both FDA and EMA thanks to the high response rate observed in the pan-cancer setting of basket trials.

The neurotrophic receptor tyrosine kinase genes NTRK1, NTRK2 and NTRK3 encode the tropomyosin receptor kinase proteins TRKA, TRKB and TRKC, respectively. These three receptors play important roles in nervous system development through their regulation of cell proliferation, differentiation, apoptosis, and survival of neurons in both the central and peripheral nervous systems. The TRK receptors are expressed abundantly in the nervous system, as well as in monocytes, lung, bone and pancreatic beta cells. TRKA, TRKB, and TRKC are most frequently activated by their primary ligands nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and neurotrophin 3 (NT-3), respectively. Once activated, the three TRK family members most frequently signal through several downstream signalling pathways, including SHC–RAS–MAPK, PI3K–AKT or PLC?–PKC. Activation of these signalling cascades results in cell programs that mediate cellular proliferation, synaptic plasticity, neurite outgrowth and repair, prevention or repair of neurodegeneration, sensory neuron maintenance or apoptosis.

The most common mechanism of oncogenic activation of TRK proteins is through genomic rearrangement and the creation of a gene fusion. This causes the loss of some of the extracellular domain of TRK, which likely contains the critical regulatory domains, thereby resulting in constitutive activation of the kinase. These oncogenic fusions, indeed, involve the carboxy-terminal kinase domain, or 3’, of TRK and the amino-terminal region, or 5’, of various partner genes. TRK fusions lead to overexpression of the chimeric proteins, resulting in constitutively active upstream, ligand-independent downstream signalling. To date, over 80 different fusio