ETS variant transcription factor 6-Neurotrophic receptor tyrosine kinase type 3 fusion protein (ETV6-NTRK3) (ETV6-NTRK3)

The ETV6-NTRK3 fusion is a chimeric oncoprotein resulting from a t(12;15)(p13;q25) chromosomal translocation that joins the 5' portion of the ETV6 gene with the 3' portion of the NTRK3 gene [1, 3]. This fusion protein consists of the N-terminal sterile alpha motif (SAM) dimerization domain of the ETS variant transcription factor 6 (ETV6) and the C-terminal protein tyrosine kinase domain of the neurotrophic receptor tyrosine kinase type 3 (NTRK3) [1, 6]. The SAM domain facilitates ligand-independent constitutive dimerization, leading to the continuous activation of the NTRK3 kinase domain and subsequent stimulation of downstream signaling pathways, including RAS/MAPK, PI3K/AKT, and JAK/STAT [1, 5]. This aberrant signaling drives uncontrolled cell proliferation and survival, making the fusion a potent oncogenic driver in various malignancies such as infantile fibrosarcoma, secretory breast carcinoma, and certain leukemias [2, 3, 12]. Therapeutic targeting of the ETV6-NTRK3 fusion is primarily achieved through the use of small-molecule tyrosine kinase inhibitors (TKIs) like larotrectinib and entrectinib, which compete with ATP for the kinase binding site [4, 10]. These drugs have demonstrated significant clinical efficacy across multiple tumor types harboring NTRK fusions, leading to their approval as tissue-agnostic therapies [4, 10]. Despite high initial response rates, patients often develop acquired resistance through secondary mutations in the NTRK3 kinase domain, such as the G623R solvent front mutation [4, 11]. Next-generation TRK inhibitors, including selitrectinib and repotrectinib, are designed to overcome these resistance mechanisms and provide durable clinical benefit [2, 11].

Other names

TEL-TRKCETV6-NTRK3 oncoproteinETV6-NTRK3 chimeric proteinEN fusiont(12;15)(p13;q25) fusion

ATP-competitive inhibition of the TRK kinase domain, which suppresses constitutive downstream signaling through the MAPK, PI3K/AKT, and JAK/STAT pathways [1, 4, 12].