Tropomyosin 3-Tropomyosin receptor kinase A fusion protein (TPM3-TRKA) (TPM3-TRKA)

The Tropomyosin 3-Tropomyosin receptor kinase A (TPM3-TRKA) fusion protein is an oncogenic driver resulting from a chromosomal rearrangement, typically an inversion on chromosome 1, that fuses the 5' end of the TPM3 gene with the 3' end of the NTRK1 gene (Amatu et al., 2016). This fusion leads to the production of a chimeric protein where the coiled-coil domain of TPM3 mediates constitutive, ligand-independent dimerization and activation of the TRKA tyrosine kinase domain (Cocco et al., 2018). The resulting aberrant signaling activates downstream pathways, including MAPK/ERK, PI3K/AKT, and PLC-gamma, which promote cell proliferation, survival, and epithelial-mesenchymal transition (Vaishnavi et al., 2015). TPM3-TRKA fusions are identified across a variety of adult and pediatric solid tumors, most notably in colorectal cancer, papillary thyroid carcinoma, and non-small cell lung cancer (Drilon et al., 2018). Therapeutic targeting of this fusion with selective TRK inhibitors, such as larotrectinib and entrectinib, has demonstrated high clinical efficacy and durable responses regardless of tumor histology (Doebele et al., 2020). Despite initial success, clinical management is often complicated by the emergence of acquired resistance mutations within the TRKA kinase domain, such as the G595R solvent front mutation, which necessitates the development of next-generation inhibitors like selitrectinib (Drilon et al., 2017).

Other names

TPM3-NTRK1 fusionTPM3-TRKA chimeric proteinTRK-T1Tropomyosin 3-NTRK1 chimeric protein

Competitive inhibition of the adenosine triphosphate (ATP) binding site of the TRK kinase domain, preventing autophosphorylation and downstream signaling.