Emerging Targeted Therapy for Tumors with NTRK Fusion Proteins

Abstract

The oncogenesis-promoting role of chromosomal rearrangements for several hematologic and solid malignancies is well recognized. However, identifying targetable, actionable, and druggable chromosomal rearrangements remains a challenge. Targeting gene fusions and chromosomal rearrangements is an effective strategy in treating gene rearrangement-driven tumors. The NTRK (Neurotrophic Tyrosine Receptor Kinase) gene family encodes three tropomyosin-related kinase (TRK) receptors that preserve central and peripheral nervous system development and function. NTRK genes, similar to other genes, are subject to alterations, including fusions. Preclinical studies have demonstrated that TRK fusion proteins promote oncogenesis by mediating constitutive cell proliferation and survival. Several clinical trials have estimated the safety and efficacy of TRK fusion kinase receptor inhibitors and have demonstrated encouraging antitumor activity in patients with NTRK-rearranged malignancies. Specifically, larotrectinib and entrectinib have emerged as potent, safe, and promising TRK inhibitors. Herein, we discuss the potential oncogenic characteristics of TRK fusion proteins in various malignancies and highlight ongoing clinical trials of kinase inhibitors targeting them.