Neurotrophic receptor tyrosine kinase 1 (NTRK1), Neurotrophic receptor tyrosine kinase 3 (NTRK3), and ROS proto-oncogene 1 (ROS1) fusion proteins (NTRK/ROS1)

The target "TPM3-TRKA fusion / TRKC / GOPC-ROS1 fusion" represents a composite of oncogenic drivers involving the Neurotrophic Receptor Tyrosine Kinase (NTRK) family and the ROS1 proto-oncogene. TPM3-NTRK1 (TRKA) and GOPC-ROS1 are chimeric proteins resulting from chromosomal translocations that lead to the constitutive activation of their respective kinase domains, driving uncontrolled cell proliferation and survival via the MAPK/ERK and PI3K/AKT pathways (Drilon et al., 2020; Vaishnavi et al., 2013). Neurotrophic receptor tyrosine kinase 3 (TRKC) is a transmembrane receptor essential for nervous system development that can also promote tumorigenesis when fused or overexpressed (UniProtKB P04629, Q16288). These genetic alterations are found across a wide variety of adult and pediatric solid tumors, making them key targets for "tumor-agnostic" precision medicine (FDA, 2019). Therapeutic agents like entrectinib are designed as potent, CNS-active inhibitors of these kinases, effectively blocking the survival signals in fusion-positive cancer cells (Ardini et al., 2016). Clinical monitoring of these targets often involves next-generation sequencing to identify the specific gene fusions in patient samples, which is critical for selecting patients for targeted therapy (FDA, 2019). The inhibition of these proteins has shown significant clinical efficacy, although resistance can develop through secondary mutations in the kinase domains (Drilon et al., 2020).

Other names

TPM3-TRKA fusionTRKCGOPC-ROS1 fusionTPM3-NTRK1 fusionNeurotrophic receptor tyrosine kinase 3NTRK3ROS1 fusionTRK/ROS1 fusions

ATP-competitive inhibition of the kinase domains of TRKA, TRKB, TRKC, and ROS1 proteins, preventing downstream oncogenic signaling.