High affinity nerve growth factor receptor (TRKA) F589L (TRKA F589L)

TRKA F589L is a specific acquired resistance mutation in the High affinity nerve growth factor receptor (TRKA), which is encoded by the NTRK1 gene (UniProt P04629). This mutation involves a substitution of phenylalanine with leucine at position 589, a site known as the gatekeeper residue within the ATP-binding pocket of the kinase domain (Russo et al., 2020, Cancer Discovery). In patients with NTRK fusion-positive cancers, this structural alteration sterically hinders the binding of first-generation TRK inhibitors such as larotrectinib and entrectinib, leading to clinical resistance and disease progression (Drilon et al., 2017, Cancer Discovery). TRKA normally functions as a receptor for nerve growth factor (NGF) and is essential for the development and survival of specific neuronal populations (Amatu et al., 2019, ESMO Open). The F589L mutation is a key target for second-generation TRK inhibitors like selitrectinib and repotrectinib, which are designed to maintain efficacy despite the gatekeeper substitution (NCI Drug Dictionary). Monitoring for this mutation via liquid biopsy or tissue sequencing is critical for managing patients who relapse on initial TRK-targeted therapy (Marchiò et al., 2019, Annals of Oncology).

Other names

NTRK1 F589LTropomyosin receptor kinase A F589LTRKA gatekeeper mutationp.Phe589Leu

ATP-competitive tyrosine kinase inhibition