Translocated promoter region–Tropomyosin receptor kinase A fusion (TPR-TRKA)

The TPR–TRKA fusion is an oncogenic chimeric protein formed by the chromosomal rearrangement of the TPR (Translocated Promoter Region) gene and the NTRK1 (Neurotrophic Receptor Tyrosine Kinase 1) gene, typically via a pericentric inversion on chromosome 1 [1.2.2, 1.3.1]. This fusion results in the constitutive, ligand-independent activation of the TRKA tyrosine kinase domain, which is joined in-frame to the N-terminal dimerization domain of TPR [1.1.1, 1.2.4]. The resulting oncoprotein drives aberrant signaling through the MAPK, PI3K/AKT, and PLCγ pathways, leading to uncontrolled cell proliferation and survival [1.2.1, 1.3.3]. TPR–TRKA fusions are primarily associated with papillary thyroid carcinoma, where they were first identified as the TRK-T1 oncogene, but they have also been detected in other malignancies such as pancreatic and colorectal cancers [1.1.2, 1.2.2, 1.3.2]. As a member of the NTRK fusion family, this protein is a highly actionable therapeutic target for first-generation TRK inhibitors like larotrectinib and entrectinib, which provide durable responses in patients across various tumor types [1.1.3, 1.4.3]. These drugs act by competitively binding to the ATP-binding site of the kinase domain, thereby blocking the oncogenic signaling cascade [1.1.1, 1.1.4]. However, clinical efficacy can be limited by the development of acquired resistance mutations in the kinase domain, necessitating the use of next-generation inhibitors like repotrectinib [1.1.3, 1.3.1].

Other names

TPR-NTRK1 fusionTRK-T1TPR-TRKA oncoproteinTranslocated promoter region–Neurotrophic receptor tyrosine kinase 1 fusion

ATP-competitive inhibition of the TRK kinase domain, preventing autophosphorylation and downstream oncogenic signaling.