The Research Progress of Neurotrophic Tyrosine Receptor Kinase (NTRK) Gene Fusions and Tropomyosin Receptor Kinase (TRK) Inhibitors: A Narrative Review

Abstract

NTRK gene is responsible for encoding TRK, which consists of three family members: NTRK1, NTRK2, and NTRK3. These family members encode different proteins known as TRKA, TRKB, and TRKC, respectively. NTRK fusion genes are the clearest driving factor for carcinogenesis. NTRK gene fusion detection and TRK inhibitors are effective measures for the treatment of malignant tumors. The development of anti-tumor drugs targeting TRK proteins has been favored by various scientific research institutions and pharmaceutical companies. The first-generation TRK inhibitors, larotrectinib and entrectinib, have been approved for the treatment of pediatric and adult patients with metastatic or locally advanced solid tumors harboring NTRK fusion proteins, demonstrating remarkable anticancer efficacy in clinical settings. However, the issue of acquired resistance to TRK inhibitors has emerged. Currently, efforts are underway to develop next-generation TRK inhibitors based on sequence, structural, and kinetic methodologies, as well as to explore the intracellular signaling pathways of TRK and the mechanisms underlying resistance. The main focus of this review was to discuss the fusion of NTRK genes and the application of TRK inhibitor treatment.