High affinity nerve growth factor receptor (TRKA) G667C (TRKA G667C)

High affinity nerve growth factor receptor (TRKA) G667C is a mutated variant of the TRKA protein, a receptor tyrosine kinase encoded by the NTRK1 gene (UniProt P04629). The G667C mutation is located in the solvent front of the kinase domain, where it replaces a glycine residue with a bulkier cysteine residue. This structural change creates steric hindrance that prevents first-generation TRK inhibitors, such as larotrectinib and entrectinib, from accessing the ATP-binding pocket (Drilon et al., 2018). Consequently, G667C is a major mechanism of acquired resistance in patients with TRK fusion-positive cancers undergoing treatment. Under normal physiological conditions, TRKA facilitates neuronal survival and differentiation by binding to nerve growth factor (NGF) and activating downstream signaling pathways like MAPK and PI3K. In the context of malignancy, NTRK1 fusions lead to constitutive kinase activity, driving uncontrolled cell growth (Cocco et al., 2018). Therapeutic strategies for this target involve next-generation inhibitors like selitrectinib and repotrectinib, which are designed to bind effectively despite the G667C mutation. Monitoring for this mutation via liquid biopsy or next-generation sequencing is essential for managing treatment progression in oncology patients.

Other names

NTRK1 G667CTropomyosin receptor kinase A G667Cp140-TrkA G667CTRKA solvent front mutation G667C

Tyrosine kinase inhibition; specifically, next-generation inhibitors utilize a macrocyclic or compact structure to bypass steric hindrance caused by the G667C substitution in the solvent front (Cocco et al., 2018).