Tropomyosin 3-Neurotrophic receptor tyrosine kinase 1 fusion protein (TPM3-NTRK1)

The TPM3-NTRK1 fusion protein is an oncogenic chimeric protein resulting from the fusion of the 5' end of the Tropomyosin 3 (TPM3) gene with the 3' end of the Neurotrophic Receptor Tyrosine Kinase 1 (NTRK1) gene [1]. This rearrangement typically occurs via an intra-chromosomal inversion on chromosome 1q, which places the coiled-coil domain of TPM3 upstream of the NTRK1 tyrosine kinase domain [2]. The TPM3 moiety facilitates constitutive dimerization of the fusion protein, leading to ligand-independent activation of the TRKA kinase [3]. This activation triggers downstream signaling cascades, including the MAPK/ERK, PI3K/AKT, and PLC-gamma pathways, which drive uncontrolled cell proliferation and survival [4]. TPM3-NTRK1 was the first TRK fusion identified in human cancer and is found in various malignancies, including colorectal cancer, thyroid cancer, and lung adenocarcinoma [5]. Therapeutic targeting of this fusion is achieved through small-molecule TRK inhibitors like larotrectinib and entrectinib, which have demonstrated high response rates in patients harboring NTRK fusions regardless of tumor type [6]. However, clinical challenges include the emergence of acquired resistance mutations in the kinase domain, such as the G595R solvent front mutation, necessitating the development of next-generation inhibitors like repotrectinib [7].

Other names

TPM3-TRKATRK-T1TRK oncogeneTPM3-NTRK1 rearrangement

Competitive inhibition of the ATP-binding site of the NTRK1 kinase domain, preventing autophosphorylation and subsequent activation of downstream oncogenic signaling pathways.