Tropomyosin receptor kinase (TRK) (TRK)

The Tropomyosin receptor kinase (TRK) family consists of three transmembrane receptor tyrosine kinases—TrkA, TrkB, and TrkC—encoded by the NTRK1, NTRK2, and NTRK3 genes, respectively [UniProt: P04629, Q16620, Q16288]. These receptors are primarily expressed in the nervous system, where they play critical roles in neuronal development, differentiation, and survival by binding to neurotrophins like nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), and neurotrophin-3 (NT-3) [PMID: 26865438]. In oncology, chromosomal rearrangements leading to NTRK gene fusions result in the constitutive activation of TRK signaling, driving the growth of various adult and pediatric solid tumors regardless of the tissue of origin [PMID: 30463006]. This oncogenic driver is found in a wide range of cancers, including rare types like infantile fibrosarcoma and common types like lung or colorectal cancer. Drugs like larotrectinib and entrectinib have been developed as highly selective TRK inhibitors, demonstrating significant efficacy in treating tumor-agnostic cancers harboring these fusions. These inhibitors work by blocking the ATP-binding site of the kinase domain, thereby halting downstream proliferative signals. However, therapeutic challenges include the development of acquired resistance mutations, such as solvent front mutations, which necessitate the development of next-generation inhibitors like repotrectinib. Additionally, because TRK signaling is vital for normal neurological function, patients may experience side effects like dizziness or cognitive changes [PMID: 31110040].

Other names

Neurotrophic tyrosine kinase receptorNTRKTrkATrkBTrkCNTRK1NTRK2NTRK3

Competitive inhibition of the adenosine triphosphate (ATP) binding site within the TRK kinase domain, preventing autophosphorylation and subsequent activation of downstream signaling cascades such as MAPK, PI3K/Akt, and PLC-gamma [PMID: 29466598].